WORLD HEALTH ORGANIZATION DEVELOPING DOSING GUIDANCE FOR NEW AND UPCOMING FORMULATIONS OF PAEDIATRIC ANTIRETROVIRALS IN LINE WITH TREATMENT 2.0 PRIORITIES Paediatric Antiretroviral Working Group Geneva, Switzerland 25-26 October 2011 Meeting Report
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DEVELOPING DOSING GUIDANCE FOR NEW AND UPCOMING FORMULATIONS OF PAEDIATRIC ANTIRETROVIRALS IN LINE WITH TREATMENT 2.0 PRIORITIES WHO/HIV/2012.8 (09/07/2012) © World Health Organization 2012 All rights reserved. Publications of the World Health Organization are available on the WHO web site (www.who.int) or can be purchased from WHO Press, World Health Organization, 20 Avenue Appia,1211 Geneva 27,Switzerland (tel.: +41 22 791 3264; fax: +41 22 791 4857; e-mail: bookorders@who.int). Requests for permission to reproduce or translate WHO publications – whether for sale or for noncommercial distribution – should be addressed to WHO Press through the WHO web site (http://www.who.int/about/licensing/copyright_form/en/index.html). The designations employed and the presentation of the material in this publication do not imply the expression of any opinion whatsoever on the part of the World Health Organization concerning the legal status of any country, territory, city or area or of its authorities, or concerning the delimitation of its frontiers or boundaries. Dotted lines on maps represent approximate border lines for which there may not yet be full agreement. The mention of specific companies or of certain manufacturers’ products does not imply that they are endorsed or recommended by the World Health Organization in preference to others of a similar nature that are not mentioned. Errors and omissions excepted, the names of proprietary products are distinguished by initial capital letters. All reasonable precautions have been taken by the World Health Organization to verify the information contained in this publication. However, the published material is being distributed without warranty of any kind, either expressed or implied. The responsibility for the interpretation and use of the material lies with the reader. In no event shall the World Health Organization be liable for damages arising from its use.
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Contents Abbreviations and Acronyms...........................................................................3 Executive Summary.........................................................................................4 Background & Context....................................................................................6 Meeting Objectives..........................................................................................7 Methodology of Meeting……….........................................................................8 Participants………………………………………………………………………………………..8 Findings and Recommendations.....................................................................9 A. B. C. D. E. F.
LPV/r formulations for infants: use of sprinkles and storage of syrups TDF formulations for children: child specific formulations and scored adult tablets EFV dosing in children under 3 years and under 10kg New paediatric PI drugs: proposed ratios of DRV and ATV with RTV NVP lead-in dosing for young children: recommendations based on existing evidence Differences in FDA and WHO dosing recommendations
Conclusion and next steps...............................................................................24 Annex A: Meeting Agenda.................................................................................25 Annex B: Meeting Participants.........................................................................27
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Abbreviations and Acronyms 3TC API ARV ART ATV AUC CHAPAS DHHS DRV EFV FDA FDC FTC HIV IMPAACT LPV NNRTI NRTI NVP PAWG PI PK POC RTV TDF VL WHO Lamivudine Active Pharmaceutical Ingredients Antiretroviral Antiretroviral Therapy Atazanavir Area under the plasma concentration-time curve Children with HIV in Africa - Pharmacokinetics and Adherence of Simple Antiretroviral Regimens trial U.S. Department of Health and Human Services Darunavir Efavirenz Food and Drug Administration Fixed-dose Combination Emtricitabine Human immunodeficiency virus International Maternal Paediatric Adolescent AIDS Clinical Trials Group Lopinavir Non-nucleoside reverse transcriptase inhibitor Nucleoside reverse transcriptase inhibitor Nevirapine Paediatric Antiretroviral Working Group Protease Inhibitor pharmacokinetics Point of Care Ritonavir Tenofovir disoproxil fumarate Viral Load World Health Organization
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Executive Summary As access to paediatric antiretroviral (ARV) treatment expands worldwide, there is an increasing need to improve and simplify formulations for children. In moving towards the joint UNAIDS/ World Health Organization (WHO) Treatment 2.0 initiative, revised dosing guidance for new and current paediatric formulations will be critical to ensuring children have access to better, safer and simpler treatment. The market for paediatric ARVs is substantially smaller and more fragmented than for adults. This is as a result of the more complicated treatment needs of children. As children grow and move through infancy, childhood and adolescence, the optimal dosing strategy changes. Infants in particular require formulations such as syrups and dispersible tablets, which are difficult to administer and pose additional supply chain challenges in resourceconstrained settings. Furthermore, the development and maturation of organ systems involved in drug absorption and metabolism is influenced by age. Finally, as children are surviving longer into adolescence and adulthood, more second- and third- line regimens are needed to ensure successful and sustainable treatment throughout life. The Paediatric Antiretroviral Working Group (PAWG) was formed in 2006 to guide the development of the WHO normative guidelines for antiretroviral therapy in infants and children. The group meets regularly to update recommendations, prioritize ARVs and review dosing guidance for new and upcoming paediatric ARV formulations. Following a recent Treatment 2.0 meeting in London on the short-term priorities for ARV drug optimization, the PAWG convened in Geneva in October 2011 to discuss and revise the dosing recommendations for priority drugs identified for children in the London meeting. Clear dosing guidance from WHO is essential for policy makers and programme implementers, as well as to inform manufacturers and drug regulatory authorities. The PAWG meeting in Geneva focused on providing appropriate dosing of new ARVs by age group and weight-band, as well as advising on potential ratios of future paediatric fixed-dose combinations (FDCs). In addition, the group provided recommendations on the storage of LPV/r syrup and on Nevirapine (NVP) lead-in dosing.
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Summary of Findings and Dosing Recommendations ARV LPV/r Proposed Recommendation • LPV/r sprinkles should replace LPV/r syrup (when this formulation is available and pending pharmacokinetics (PK) studies to support the tentative dosing schedule) • Emphasize the importance of cold chain storage of LPV/r syrup up to the point of dispensing • Develop dual TDF/3TC FDC for paediatric use – either by scoring adult tablets if feasible or by manufacturing a child specific tablet containing TDF 75mg and 3TC 75mg (1/4 scale down of adult) • Develop triple TDF/3TC/EFV FDC for paediatric use – either by scoring adult tablets if feasible or by manufacturing a child-specific tablet containing TDF 75mg and 3TC 75mg (Efavirenz) EFV 150mg (1/4 scale down of adult) • Develop dual TDF/FTC FDC for paediatric use by manufacturing a child specific tablet containing TDF 75mg and FTC 60mg (this is not a scale down of the adult formulation) • Develop triple TDF/FTC/EFV FDC for paediatric use by manufacturing a child specific tablet containing TDF 75mg FTC 60mg and EFV 150mg (this is not a scale down of the adult formulation) • For children over 10kg, the ratio of DRV (Darunavir ) to RTV (Ritonavir) should be 6:1 dosed twice daily • For children over 10kg, the ratio of ATV to RTV should be 3:1 dosed once daily • Recommend full dose NVP as an alternative to lead-in dosing in children under 3 years of age starting NVP-based treatment for the first time.
TDF
DRV/r ATV/r NVP
* Tablets scored into two halves on one side and three thirds on the other.
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Background and Context Launched by UNAIDS and WHO in 2010, Treatment 2.0 is an initiative designed to achieve and sustain universal access to HIV treatment and care. The Treatment 2.0 initiative is supported by 5 pillars, or priority work areas, which address the need for innovation and efficiency gains, greater effectiveness, and more accessible HIV services. Treatment 2.0 Priority Work Areas: 1. 2. 3. 4. 5. Optimize Drug Regimens Provide Access to Point-of-Care (POC) Diagnostics Reduce Costs Adapt Delivery Systems Mobilize Communities
Optimizing drug regimens is a cornerstone of Treatment 2.0. The goal is to develop and promote drug regimens that are simple, effective, low in toxicity and have high barriers to drug resistance. A key part of drug optimization involves establishing optimal dosing of ARVs for adults and children, encouraging the use of FDCs and increasing access to newer, more effective formulations. Paediatric treatment coverage is lagging far behind that of adults and there is an urgent need to close the treatment gap. Simplifying and harmonizing paediatric regimens with adult therapies would significantly aid in the programmatic scale up of paediatric treatment coverage by making it easier for non-expert clinicians who are familiar with adult Antiretroviral Therapy (ART), to also be able to prescribe to children. The PAWG is a technical working group of the WHO that helps develop formulation and dosing guidance on ARVs for children with HIV. The market for paediatric HIV treatment is smaller than for adults and highly fragmented due the availability of multiple formulations. Too many dosing forms of the same drug combinations cause confusion at the programmatic level, as well as difficulties for supply chain management within countries. In addition, variability and complexity of treatment recommendations for different age groups adds to the confusion and market fragmentation. These factors create a disincentive for industry to develop and produce paediatric ARVs, which is compounded by the near elimination of HIV infection in infants and young children in the United States and Europe. Consequently, there is very low demand in these markets. This issue needs to be addressed in two ways. First, for formulations that already exist, there is a need to reduce the number of options that are available to country programmes by focusing on those products that offer ease and simplicity for paediatric dosing, without compromising quality or regimen choice. Second, for formulations that have yet to be produced, it is important to try and pinpoint the most critically needed products that align, as much as possible, with adult options in order to sustain the paediatric market. A number of FDCs have been developed to lower the pill burden and simplify treatment in resource-constrained settings for adults and children. It is important to note that when using adult FDCs for children, the proportions required for each drug may need to be different. For these reasons, there is an urgent need for clear recommendations on the use of scored adult tablets and for the development of FDCs for children, as well as appropriate PK studies showing that paediatric FDCs deliver target drug levels. 7
At a recent Treatment 2.0 meeting in London, an expert panel defined a number of priority formulations that need to be developed for children. An important goal of this PAWG meeting was to develop detailed paediatric dosing and formulation guidance on the priority ARVs identified in the London meeting1. The 2010 WHO antiretroviral therapy guidelines for children include Annex E on dosing recommendations for each ARV based on weight-bands. With the development of new products and emerging data on the PK of ARVs in children, this annex needs to be modified and updated in the next edition of WHO’s guidelines. The outcomes of the meeting described in this report will directly inform the new guidelines, as well as provide up-to-date guidance to manufacturers and policy markers.
Meeting Objectives The key objectives of the meeting were to develop guidance on the current use of and future development of paediatric formulations in line with the principles of Treatment 2.0. Specifically, the aims of the meeting were: A. B. C. D. E. F. To provide an update on the development of a new formulation for LPV/r and offer new guidance on storage of LPV/r syrup. In line with the short term optimization priorities, to determine the best TDF formulations for children To determine the best ratio of ATV/r to be developed into a FDC formulation for children. To determine the best ratio of DRV/r to be developed into a FDC formulation for children. To discuss the impact of NVP lead-in dosing for young children. To discuss discrepancies between dosing guidance from WHO and the Food and Drug Administration (FDA)
Methodology of Meeting The meeting was a mixture of plenary presentations and group discussions to review the results of recent studies, the analysis of unpublished data, and the outputs of dosemodeling exercises. The agenda is outlined in Annex A.
Meeting Participants The meeting brought together clinicians who deliver paediatric HIV treatment and care, paediatric pharmacologists, clinical researchers, partners and HIV programme implementers. The full list of participants is described in Annex B. All participants declared no conflict of interest.
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Short term priorities for antiretroviral drug formulation: meeting report. London, UK 18-19 April 2011. http://whqlibdoc.who.int/publications/2011/9789241501941_eng.pdf 8
Findings and Recommendations A. LPV/r Formulations for Infants Uptake of LPV/r as a first line drug in children is increasing in the developing world, albeit slowly and only in selected settings. Based on a recent WHO Universal Access survey, LPV/r is used in 12.2% of all first-line regimens in children – an increase from 9% in 2009. To date, the vast majority (97%) of children using LPV/r in first-line therapy are in South Africa. LPV/r is the most commonly used protease inhibitor (PI) in paediatric patients on second-line therapy. As the use of LPV/r in paediatric populations expands, there is an increasing need for improved formulations for younger children. The current liquid formulation for infants is unpleasant tasting and has a high alcohol concentration (42%). Moreover, LPV/r syrup requires refrigeration, making it challenging to use in resource-limited settings. Crushing tablet LPV/r formulations is not recommended but it is often done in practice because of the difficulties associated with swallowing whole tablets in the youngest children. A recent study found that crushed tablets decreased the area under the concentration-time curve (AUC) of both LPV and RTV by approximately 40% compared to whole tablets. 2 Alternative formulations such as the newly developed LPV/r “sprinkles” (Figure 1), which taste better and do not require cold-chain transport and storage, are urgently needed in resource-limited settings. The Children with HIV in Africa – Pharmacokinetics and Adherence of Simple Antiretroviral Regimens (CHAPAS) 2 trial is currently underway to compare the PK and acceptability of LPV/r in sprinkle, tablet and syrup form in HIVinfected African children (Box 1). The trial has begun to enroll patients and results should become available in the first half of 2012. This data will help inform dosing recommendations for LPV/r sprinkles in infants and children. Figure 1: LPV/r Sprinkles for Children
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Best B.M. et al., (2011) Pharmacokinetics of Lopinavir/Ritonavir Crushed Versus Whole Tablets in Children. J Acquir Immune Defic Syndr 58(4) 9
Box 1: CHAPAS 2 Trial Details and Status Study Design: Open, randomised, controlled, phase I, crossover trial Study Hypothesis: 1. There is no difference in blood drug levels (overall area under the plasma concentration time curve (AUC) and Cmin) among children aged 4-13 years taking LPV/r or tablet formulations of ritonavir-boosted-lopinavir together with food and also compared to historical controls. 2. There is no difference in blood drug levels (overall area under the plasma concentration time curve (AUC) and Cmin) among infants (under 1 year) taking syrup or sprinkle formulations of ritonavir-boosted-lopinavir together with food according to WHO doses and weight bands and also compared to historical controls. Country: Uganda Status of Trial: Ongoing, recruiting participants Size: 24 children age 4-12 years and 16 children 3-12 months; amendment submitted to ethics for a further cohort of 24 children age 1-4 years randomized to liquid or sprinkle with crossover and dual PK evaluation. Anticipated End Date: 01/03/2012 Contact: Professor Diana Gibb, MRC UK Table 1: Proposed Dosing Schedule of LPV/r Sprinkle Formulation LPV/r Formulation and strength Number of capsules or ml by weight-band morning and evening 3-5.9kg am Sprinkle (40/10mg) Liquid (80/20mg/ml) 2 or 3* 1 or 1.5# Pm 2 or 3* 1 or 1.5# 6-9.9kg am 3 1.5 pm 3 1.5 10-13.9 kg am 4 2 pm 4 2 14-19.9kg am 5 2.5 pm 5 2.5 20-24.9 kg am 6 3 pm 6 3
* LPV/r sprinkle: for 3-3.9kg use 2 capsules am and 2 capsules pm; for 4-5.9kg use 3 capsules am and 3 capsules pm # LPV/r liquid: for 3-3.9 kg, use 1ml am and 1ml pm; for 4-5.9kg use 1.5ml am and 1.5ml pm
Proposed Recommendations around LPVr 1. When regulatory approval for LPV/r sprinkles is obtained - advocate for programmes to replace syrup with sprinkles. 2. Dosing schedule proposed for LPV/r sprinkles outlined in table 1 and will be confirmed by the results of CHAPAS 2.
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B. LPV/r Syrup Storage The PAWG discussed in detail concerns about the heat stability of LPV/r syrup based on a letter from the manufacturer, which states that at a temperature of 26-30°C LPV/r syrup is stable for 8 days in total if there is no hand off and for 1 day at patient level. There is limited data available to determine the impact of higher temperatures on LPV/r concentration and chemical stability. In one small study, 3 sample batches of LPV/r capsules and liquid were stored at temperatures of 35oC and 45oC for up to 12 weeks. The results show that at high temperatures evaporation losses from the liquid result in an increase in both LPV and RTV concentrations. The concentration of breakdown products or excipients was not measured in this study3. The PAWG felt that additional data was important to establish the stability of LPV/r liquid at higher temperatures. However, dosing guidance should reflect the importance of coldstorage up to the point of dispensing. In addition, patients and caregivers should be instructed on how best to keep bottles cool in the home. Proposed Recommendations around LPVr 1. Change the storage recommendations to emphasize the need for cold chain storage up to the point of dispensing. 2. Change the storage recommendations for patients to encourage them to store syrup away from direct sunlight and use other approaches to keep the bottles cool.
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Personal Communication Edmund Capparelli 11
C. TDF Formulations for Children The drive to harmonize paediatric regimens with adults and the expected approval of TDF for 2-12 year olds provided the rationale to discuss optimal TDF-containing FDCs for children4. TDF has proven potent, effective and well tolerated in adult populations. The group reviewed new data from a manufacturer-sponsored trial on the use of TDF in children over 2 years – in particular on the dose recommended and the reported renal and bone toxicities. The PAWG noted that bone and renal toxicity was observed in children and stressed the importance of ongoing studies and monitoring of cohorts of children who are treated with TDF. However, the overall benefits were felt to outweigh the risks of treatment. The PAWG felt that a dual TDF-containing FDC might be easier to manufacture and more versatile as an initial product. A triple FDC containing EFV could be developed subsequently. The ratio, tablet strength and dose of future paediatric TDF-containing FDCs were modeled using the PAWG generic tool5 to determine dose delivered against the target dose for each component of the FDC. The generic tool uses WHO weight-bands in order to harmonize with current dosing recommendations. The models assume an optimal target range between the target dose described for each drug and up to 25% above this dose
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TDF was approved subsequent to this meeting http://www.who.int/hiv/paediatric/generictool/en/ 12
I) TDF-containing Dual FDCs For a dual FDC containing TDF and 3TC, the PAWG used the tool to model both a scored adult tablet (Figure 2) and a child-specific FDC with the same drug ratio as the adult tablet (Figure 3). Both formulations could be dosed to effectively deliver target doses to children, as well as being easier and quicker for manufacturers to bring to market since the ratio of drugs would remain the same. Figures 2-3: Dose Modeling of TDF/3TC Dual FDCs Figure 2: Scored Adult Dual Tablet TDF/3TC (300/300mg) TDF 3TC
Target dose: 8mg/kg daily
Target dose: 8mg/kg daily
WHO Weight Band (KG) Dose (tablets)
10-13.9 .33
14-19.9 .5
20.24.9 .67
25-34.9 1
Figure 3: Child Dual Tablet TDF/3TC (75/75mg) – ¼ of adult strength TDF 3TC
Target dose: 8mg/kg daily Target dose: 8mg/kg daily
WHO Weight Band (KG) Dose (tablets)
10-13.9 1.5
14-19.9 2
20.24.9 2.5
25-29.9 3
30-34.9 3.5 13
When the same dose modeling approach was applied to the dual TDF/ FTC FDC, in contrast to TDF/3TC, it was noted that the adult scored tablet would likely deliver subtherapeutic doses of the FTC component in children weighing between 11kg and 20kg (see FTC graphic Figure 4).
Figure 4: Scored Adult Dual Tablet TDF/FTC (300/200mg) TDF
FTC
FTC levels low
Target dose: 6mg/kg daily Target dose: 8mg/kg daily
WHO Weight Band (KG) Dose (tablets)
10-13.9 .33
14-19.9 .5
20.24.9 .67
25-34.9 1
In order to achieve adequate dose delivered of FTC, a child-specific formulation containing TDF 75mg and FTC 60 mg would be needed (Figure 5). Figure 5: Child Dual Tablet TDF/FTC (75/60mg) TDF FTC
Target dose: 8mg/kg daily WHO Weight Band (kg) Dose (tablets) 10-13.9 1.5 14-19.9 2 20-24.9 2.5
Target dose: 6mg/kg daily
25-29.9 3
30-34.9 3.5 14
II) TDF-containing Triple FDCs The PAWG also discussed ratios for developing TDF triple FDCs containing EFV. A scaled down version of the existing adult TDF/3TC/EFV FDC could be used to effectively deliver target doses to children. Both a scored adult tablet (Figure 6) and a child-specific FDC with the same drug ratio as the adult tablet (Figure 7) were modeled using the tool. Figures 6-7: Dose Modeling of TDF/3TC/EFV Figure 6: Scored Adult Triple Tablet TDF/3TC/EFV (300/300/600mg) TDF 3TC
Target dose: 8mg/kg daily Target dose: 8mg/kg daily
EFV
Target dose: 15mg/kg daily WHO Weight Band (kg) Dose (tablets) 10-13.9 0.33 14-19.9 0.5 20-24.9 0.67 25-34.9 1
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Figure 7: Child Triple Tablet TDF/3TC/EFV (75/75/150mg) – ¼ of adult strength TDF 3TC
Target dose: 8mg/kg daily Target dose: 8mg/kg daily
EFV
Target dose: 15mg/kg daily WHO Weight Band (kg) Dose (tablets) 10-13.9 1.5 14-19.9 2 20-24.9 2.5 25-29.5 3 30-34.9 3.5
As with the adult dual FDC of TDF/FTC, a scaled down version of the adult triple FDC of TDF/FTC/EFV would not deliver adequate doses of the FTC component. However, a childspecific FDC containing TDF 75mg, FTC 60mg and EFV 150mg could be used to deliver target doses of all three components (Figure 8).
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Figure 8: Child Triple Tablet TDF/FTC/EFV (75/60/150mg) TDF 3TC
Target dose: 8mg/kg daily
Target dose: 6mg/kg daily
EFV
Target dose: 15mg/kg daily WHO Weight Band (kg) Dose (tablets) 10-13.9 1.5 14-19.9 2 20-24.9 2.5 25-29.5 3 30-34.9 3.5
The PAWG discussed the feasibility of scoring adult FDC tablets on both sides of the tablet in order to be able to divide adult tablets into halves and thirds. (See example of such a tablet in Figure 9). There was concern that while the doses delivered by third and half split tablets would be acceptable, in practice it may be difficult to manufacture, score and split large and multilayered FDC tablets in this way. It would be important to establish feasibility, PK and bioavailability data to support this dosing strategy and demonstrate equal distribution of the active pharmaceutical ingredients (API) in split parts.
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Scored adult solid formulations, such as co-formulated zidovudine and lamivudine have been approved for paediatric dosing based on models of existing PK data in children. However, these models rely on assumptions that bioavailability data produced in adults comparing solution and tablet formulations can be extrapolated to children. A crossover, open-label study as part of the ARROW trial, confirmed that zidovudine and abacavir tablets were bioequivalent to solutions in HIV-infected Ugandan children; however, lamivudine tablets resulted in approximately 50% higher exposure compared to the solution.6 The PAWG noted that manufacturers often use adult PK data for licensing and emphasized the importance of performing such PK studies in children given the potential variations between children and healthy adults.
Figure 9: An Example of Dual Scoring of a Tablet Proposed Recommendations around TDF FDC formulations for children 1. Develop dual TDF/3TC FDC for paediatric use – either by scoring adult tablets if feasible or by manufacturing a child specific tablet containing TDF 75mg and 3TC 75mg (1/4 scale down of adult). 2. Develop triple TDF/3TC/EFV FDC for paediatric use – either by scoring adult tablets if feasible or by manufacturing a child-specific tablet containing TDF 75mg and 3TC 75mg EFV 150mg (1/4 scale down of adult). 3. Develop dual TDF/FTC FDC for paediatric use by manufacturing a child specific tablet containing TDF 75mg and FTC 60mg (this is not a scale down of the adult formulation). 4. Develop triple TDF/FTC/EFV FDC for paediatric use by manufacturing a child specific tablet containing TDF 75mg FTC 60mg and EFV 150mg (this is not a scale down of the adult formulation).
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Kasirye P. et al., ‘Pharmacokinetics of oral solution versus tablet formulation varies with antiretroviral drug in the target population of HIV-1 infected children. ARROW trial. (not yet published). 18
D. EFV Dosing EFV is widely recommended as an NNRTI of choice in first-line therapy due to its potent antiviral activity, long half-life (allowing once-daily dosing), and potential to be used in conjunction with TB treatment. However, substantial variability in EFV exposure between individuals raises concern about the appropriate dosing for children. If under-dosed, subtherapeutic levels of EFV can lead to resistance, whereas long-term overdosing could increase the risk of adverse effects. Currently, dosing in infants under 3 years has not been established. Recent PK studies in children show that clearance of EFV is significantly affected by the expression of hepatic CYP2B6, the principle enzyme responsible for metabolizing EFV. Changes in hepatic enzyme activity are known to differ with age, with younger children showing greater activity. As a result, optimal dosing of EFV in infants and children is particularly challenging to establish. One concern is that younger children may be at a higher risk of developing resistance because of higher clearance rates leading to subtherapeutic plasma levels.7 By contrast, children that have certain genetic polymorphisms of CYP2B6 may metabolize EFV poorly, which is known to result in high plasma concentrations (Figure 10)8. A higher prevalence of CYP2B6 polymorphisms have been reported in patients with African descent, highlighting the need for genotypic-driven dose optimization studies in these populations. Figure 10: IMPAACT P1070 Trial: Impact of CYP2B6 Genotype
CYP2B6 Polymorphisms: CYP2B6 EM= “extensive” metabolism; CYP2B6 PM= “poor” metabolism
Although individualized, concentration-targeted dosing would be beneficial for younger patients, the logistics of this would be difficult in resource-constrained settings. Nonetheless, the group discussed how higher doses of EFV would be needed to ensure adequate dosing in young children, who would then transition to lower paediatric doses. It was concluded that currently there is no dose that can uniformly be given to children but
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Saitoh A., et al., (2007) Efavirenz Pharmacokinetics in HIV-1-infected children are Associated with CYP2B6-G516T Polymorphism. J Acqui Immune Defic Syndr 45(3) 8 Capparelli E.V. (2011) EFV in Young Children - An update in infants and Children < 3 years. PAWG Presentation 25-26th October, WHO Geneva 19
ongoing PK studies, including the IMPAACT P1070 trial, will provide the data needed to make concrete recommendations in future9.
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Rakhmanina NY. & van der Anker JN. (2010) Efavirenz in the Therapy of HIV Infection. Expert Opin Drug Metab Toxicol. 6(1) 20
E. New Paediatric PI Drugs - DRV/r and ATV/r Dosing There is an urgent need to develop more PI drugs for use in children. ATV/r is a candidate for future second-line therapy and possibly as part of a first-line regimen in infants. It’s lower cost and potential for once daily dosing makes it a promising drug for the future. DRV/r is the PI of choice following LPV/r or ATV/r failure and would be valuable as a thirdline drug but also potentially as second-line therapy in young children failing first-line treatment with LPV/r. The group reviewed the dosing guidance for DRV/r and ATV/r recommended for children in the United States. Both ATV/r and DRV/r are currently only licensed for use in children aged 6 years and above. Although an ATV/r FDC was recently tentatively approved by the US FDA, neither ATV/r nor DRV/r is currently available as a co-formulated FDC for children. There are plans to extend the licensing of both DRV and ATV to children aged 3 years and above, and 3 months and above, respectively. The PAWG discussed in detail the appropriate dosing of ATV and DRV, and the best ratio of RTV to achieve maximal boosting. The group considered data that has been used to inform the US Department of Health and Human Services (DHHS) guidelines, additional PK data on ATV and DRV in children, and dose-models developed using the generic tool. In children over 10kg, there is no evidence to suggest that the ratio of RTV to either ATV or DRV needs to be different to that in adults. Although the current approved dosing recommendations for children call for a higher dose of RTV relative to both DRV and ATV (Tables 2 and 3), this is based on convenience and the availability of an easy to use heatstable tablet of RTV that contains 100mg – the full adult dose. From a pharmacokinetic perspective, given the long half-life of DRV and ATV, currently approved ratios of RTV to DRV or ATV in children are likely to be in excess of those required to inhibit the metabolism of ATV and DRV and thus achieve maximal boosting.
Table 2: Current US FDA Approved Doses and Ratios of DRV to RTV for Children aged 6 to 18 years (DRV package insert dosing) Body weight (kg) 20 – 30 30 – 40 DRV Dose (mg) 375 450 RTV Dose (mg) 50 60 Calculated DRV dose (mg/Kg) 12.5 – 18.75 11.25 – 15 Ratio 7.5:1 7.5:1 Dose Twice daily Twice Daily
600 100 <15 6:1 Twice daily Note: One daily dosing (DRV 800mg/RTV 100mg) may be used in treatment naive children aged 12-18 years and 40kg and over.
≥ 40
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Table 3: Current US FDA Approved Doses and Ratios of ATV to RTV for Children aged 6 to 18 years (ATV package insert dosing) Body weight (kg) 15 – 20 20 – 40 ATV Dose (mg) 150 200 300 RTV Dose (mg) 100 100 100 Calculated ATV dose (mg/Kg) 7.5-10 5-10 <7.5 Ratio Dose
1.5:1 2:1 3:1
Once daily Once daily Once daily
≥ 40
There is a precedent for using the same ratio in both adults and children; for LPV/r the ratio of LPV to RTV is the same across all paediatric weight-bands and between adults and children. Reducing the amount of RTV combined with ATV and DRV and using a standard ratio in all children has several benefits, including reduced costs, reduced RTVrelated toxicity, and enabling the development of a paediatric FDC 10. On the other hand, there is high degree of inter-patient variability in terms of PI metabolism in children and this creates the possibility of sub-therapeutic dosing if the amount of RTV is inadequate to overcome rapid metabolism, especially in young children. Taking all these perspectives into consideration, the group found that for children 10kg and above, it would be preferable and desirable to use current adult ratios for dosing. As these drug ratios differ from FDA labels, clinical validation of prototype DRV/r and ATV/r formulations should be prioritized.
I) ATV/r ATV/r is a promising PI for children as an alternative to LPV/r. It has some advantages over LPV/r including lower cost and ability to be dosed once daily, reducing the pill burden and simplify treatment. The dose and ratio of ATV and RTV was evaluated using the generic tool to determine the content of a paediatric FDC. Using a target dose of 7.5mg/kg for ATV and 2.5mg/kg for RTV (a ratio of 3:1), a 1/3 adult strength tablet containing ATV 100mg and RTV 33mg would deliver appropriate doses of both drugs using current WHO weight-bands and the dosing schedule given in Table 4 below. This represents a scaled down version of the current adult FDC tablet. Table 4: Dosing of ATV/r 3:1 Paediatric Tablet (100/33mg) WHO weight band (kg) Dose (tablets) 10 - 13.9 1 14 - 19.9 1 20 - 24.9 2 25 - 29.9 2 30 - 34.9 1 adult
Note: Based on once daily dosing. Adult tablet is 300/100mg once daily.
Until the approval of ATV/r for use in children over 3 months, these recommendations would only apply to children over 6 years of age where ATV/r has been fully approved.
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Hill, A. et al., (2011) Should we switch to a 50-mg boosting dose of ritonavir for selected protease inhibitors?’ J Acqui Immune Defic Syndr 58 (5) Letter to the Editor 22
II) DRV/r The doses and ratio of DRV and RTV was evaluated using the generic tool to determine the content of a paediatric FDC. Using a target dose of 15mg/kg for DRV and 2mg/kg for RTV, a tablet containing DRV 240mg and RTV 40mg (ratio of 6:1 in keeping with the adult ratio for twice daily dosing) would deliver appropriate doses of both drugs using current WHO weight-bands and the dosing schedule given in Table 5 below. Table 5: Dosing of DRV/r 6:1 Paediatric Tablet (240/40mg) WHO weight band (kg) Dose (tablets) 10 - 13.9 1 14 - 19.9 1 20 - 24.9 2 25 - 29.9 2 30 - 34.9 1 adult
Note: Based on twice daily dosing. Adult dose of DRV/r is 600/100mg twice daily.
Until the approval of DRV/r for use in children over 3 years, these recommendations would only apply to children over 6 years of age where DRV/r has been fully approved. Of note, the bioavailability of DRV/r is increased when taken with food. Cobicistat as an alternative to RTV was also discussed. There are ongoing studies to examine the utility of cobicistat as a booster for ATV and DRV. Although cobicistat licensing is now available through the Medicine’s Patent Pool, it is likely to be many years before there is data on its use in children. The PAWG emphasized the importance of this drug for the future as it is expected to have a better toxicity profile and less lipid elevation than RTV.
Proposed Recommendations on dosing and ratios for ATV/r and DRV/r 1. Pending approval of ATV/r in younger children, the PAWG recommended the development of a FDC for children containing ATV 100mg and RTV 33mg - a 1/3 strength adult tablet. 2. Pending approval of DRV/r in younger children, the PAWG recommended the development of a FDC for children containing DRV 240mg and RTV 40mg. 3. These ratios and dosing approaches should be validated in paediatric PK studies.
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F. NVP Lead-in Dosing Current recommendations for lead-in dosing of NVP are not supported by data in children. This raises the question of whether recommendations made for adults based on historic data is appropriate for children today. Considering new data from the CHAPAS and P1060 trials, as well as drug exposure modeling, the PAWG discussed whether lead-in dosing or full dose NVP from the start would in fact be better in children. In the CHAPAS trial, more rashes were associated with full dose NVP from the start, however, these were mild (grade 1 and 2), easily manageable and less frequently seen in the youngest children. Older children and those with higher CD4 count had a higher risk of developing rash. The majority of children were able to restart treatment with NVP once the rash had subsided, with only one patient switching to EFV because of rash 11. In CHAPAS 1 viral load suppression at 48 weeks were similar in children randomized to start full-dose compared to half-dose NVP. Samples are available to perform further viral load and NVP PK studies. In the P1060 cohort 2 study, which assessed treatment responses to NVP and LPV/r in children with no known prior exposure to Non-nucleoside reverse transcriptase inhibitor (NNRTIs), LPV/r outperformed NVP with a significantly higher rate of failure endpoints among children given NVP12. The authors believe this difference may be attributable to a number of factors, including in part lead-in dosing of NVP. A simulation clearance model estimating NVP levels in infants taking into account both the prevalence of genetic polymorphisms, which result in high metabolism of NVP, as well as the induction of NVP clearance, suggests that lead-in dosing is likely to result in subtherapeutic troughs in nearly half of all infants. (See Figure 11). Lower troughs during the second week of lead-in dosing is especially concerning since it may promote the development of NVP resistance, especially in patients with high viral loads. It was also noted that lead-in dosing for children can be difficult to implement in the field, causing some children to inadvertently receive lead-in (lower) doses of NVP beyond the initial two week period.
11
Mulenga V. et al., (2010) Strategies for Nevirapine Initiation in HIV-Infected Children Taking Paediatric Fixed-Dose Combination “Baby Pills” in Zambia: A Randomized Controlled Trial. Clinical Infectious Diseases 51(9) 12 + Palumbo P. (2011) NVP- vs LPV/r-based ART among HIV Infants in Resource-limited Settings: The IMPAACT P1060 Trial. CROI Boston 2011 Abstract 129LB 24
Figure 11: Modeled NVP concentration in infants dosed with or without lead in NVP With NVP lead in Without NVP lead in
The P1103 IMPAACT study is planned to formally assess NVP levels among infants with and without lead-in dosing. Considering the risks and benefits of lead-in dosing in children (Table 6) and the fact that full dose NVP would simplify treatment and avoid confusion, the PAWG recommend that children under 3 years, who are starting NVP without prior exposure, should preferably receive full dose NVP from the start of treatment. Table 6: Summary of risks and benefits of NVP lead-in dosing Benefits Risks • May reduce incidence of rash, • Complicates treatment and may result in (although data is controversial and errors because caregivers do not from adult studies; rash is an understand instructions (children may uncommon side effect in children receive lead-in dosing for longer than 2 under 3 years) weeks) • Aligns with current practice for adults • Requires additional formulations to be so providers are accustomed to the procured practice of lead-in dosing • Triple FDCs cannot be used from the start (requires dual FDC or single doses resulting in high pill burden) • May result in sub-therapeutic dosing which in the context of high Viral Load (VL) could predispose to resistance and treatment failure* (although no evidence of this in CHAPAS 1 trial) • Younger children tend to have high clearance rates, therefore subtherapeutic dosing is probable* FDA Clinical Review - NVP (Boehringer Ingelheim Pharmaceuticals) http://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/DevelopmentResources/ucm0 72777.pdf
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Proposed Recommendation on NVP lead-in dosing in young children 1. Recommend full dosing NVP as an alternative to lead-in dosing in children under 3 years of age starting NVP-based treatment. 2. Review results of P1103 as soon as these are available to determine the strength of these recommendations. 3. In the interim, recommend further viral load and PK studies on CHAPAS 1 stored samples.
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G. Differences between FDA and WHO Dosing Recommendations A session of the meeting involved a call to the FDA to address concerns about the differences in FDA and WHO dosing recommendations, which is causing confusion among manufacturers. This variation is based partly on differing intents and responsibilities of the two organizations; WHO seeks to create uniform dosing guidance across different formulations, which in some cases requires dosing that is “off label”, whereas the FDA seeks to assure quality by requiring dossiers from generic suppliers to have dosing that aligns with existing approvals from originator manufacturers. During the call, the group discussed the importance of recognizing these different perspectives and why WHO dosing guidance may differ from package inserts. Language to this effect should be incorporated into future versions of Annex E of WHO guidelines and could be modeled on similar language used within the US DHHS guidelines. In addition, the group discussed the fact that in some instances, particularly with dual and triple FDC, WHO and FDA weight-bands do not harmonize. Representatives from FDA agreed to consider an amendment for these products, which would not involve a label change. Based on a survey conducted by WHO, 86% of practitioners were using WHO weightband dosing, with almost all participants considering the weight-band dosing approach to be easier to use and the preferred option from a public health perspective. Although potential discrepancies between WHO dosing and manufacture recommended dosing were rarely checked, survey respondents expressed concern about dosing discrepancies in children between 13-24kg, for ABC dosing and dosing in older children where WHO recommends using adult tablets for children over 30kg. Overall, most respondents felt that the differences between WHO and FDA were minor. The PAWG concluded that going forwards, representatives from the FDA and WHO Prequalification group should be included in future PAWG meetings to improve communication and minimize the risk of dosing discrepancies.
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Conclusion and Next Steps Optimizing dosing of ARVs for children is particularly challenging and complicated by a variety of factors including; difficulties associated with the manufacture of child-friendly formulations, cold-chain requirements for some paediatric formulations, and fundamental differences in physiology between children and adults. ARV PK studies in adults cannot necessarily be extended to children, however, data on dosing and toxicity of ARVs in children is lacking. Over the course of this meeting, the PAWG highlighted the importance of PK studies in children, as well as the development of more paediatric drug options, particularly for the youngest children under 3 years. The PAWG provided potential dosing and ratio recommendations for the development of new and upcoming formulations of ARVs suitable for paediatric populations. The group recommended that these formulations and dosing guidance be evaluated in clinical trials.
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Annex A Meeting Agenda Day 1: October 25 Time Session topic Presenter 8.30-9.00 Registration 9.00-9.30 Welcome and overview of objectives and expected outcomes Craig McClure Overview of paediatric recommendations in London Treatment 2.0 9.30-10.00 Di Gibb meeting 10.00-10.30 Update on future WHO paediatric guidelines Shaffiq Essajee 10.30-11.00 Coffee LPVr formulations for infants Panel: 15 minutes each Country guidelines – what ARVs are national programmes using and what is the uptake of LPVr for first line therapy in infants? (Francoise Renaud-Thery) Chapas 2 – what is progress like in the trial and when can Moderated by 11.00-12.30 we expect data to submit for regulatory approval? (Di Marc Lallemant Gibb) Storage of LPVr syrup – proposed amendment to the current Annex E guidance (Janice Lee) Discussion Lunch TDF formulations for children Panel: 15 minutes each Tenofovir as a paediatric drug – summary of WHO white paper (Peter Havens) EFV in young children – Update on pk studies in children Moderated by Emily Koumans under 3 and under 10kg (Ed Caparelli) Modeling of various TDF formulations – should we aim for scored adult or child specific formulations (Shaffiq Essajee) Discussion Tea Summarizing our recommendations for the day Group Dinner location TBD Janice Lee rapporteur and
12.30-13.30
13.30-15.30
15:30-16:00 16.00-17:00 19.30 onwards
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Day 2: October 26 Time Session topic 9:00-9:30 9.30-10.45
Presenter
Overview of status of ATV/r and DRV/r – Update from the new Diana Clarke DHSS guidelines New PI drugs for children Panel: Moderated by 15 minutes each Lynne Mofensen DNDi’s initiative – bringing new paediatric PI formulations to market (Marc Lallement) Formulations of ATV/r and DRV/r – Modelling FDCs for children (Shaffiq Essajee) Discussion
10:45-11:15
Coffee NVP lead-in dosing for young children: Is it time to change the guidance? 15 minutes each P1060 and lead-in dosing of NVP – the missing link that explains it all? (Paul Palumbo) Moderated by Lead-in in infants – results of population pK modelling (Ed Mark Mirochnik Caparelli) IMPAACT P1103 – plans for a definitive answer? (Paul Palumbo) Discussion
11:15-12:45
12.45-14.00 14.00-15.30 15.30-16.00 16.00-17.00 17:00-17:15
Lunch / Optional Presentation of Outcomes of WHO Retention Meeting FDA call in session – discrepancies between FDA and WHO dosing Linda Lewis and framing the issues for further discussion Atieno Ojoo Tea Summarizing our recommendations for the day Closing remarks, next steps Diana Clarke and rapporteur Shaffiq Essajee
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Annex B List of Participants (in alphabetical order) Elaine Abrams - Mailman School of Public Health, Columbia University, USA David Burger - UMC St. Radboud Nijmegen Diana Clarke - Boston Medical Centre, Boston, USA Edmund Capparelli - University of California San Diego, USA Brian Eley - Red Cross Children’s Hospital, Cape Town, South Africa Shaffiq Essajee - Treatment and Care Unit, HIV/AIDS, WHO Secretariat HQ Marianne Gale - Médecins sans Frontières, Sydney, Australia Diana Gibb - Medical Research Council, Clinical Trials Unit, London UK Peter Havens - Children’s Hospital of Wisconsin, Milwaukee, USA Emily Koumans - Centre for Disease Control and Prevention, Atlanta, USA Marc Lallemant - Drugs for Neglected Diseases Initiative, Geneva, Switzerland Janice Lee - Médecins sans Frontières, Geneva, Switzerland Craig McClure - Treatment and Care Unit, HIV/AIDS, WHO Secretariat HQ Tammy Meyers - Chris Hani Baragwanath Hospital, Johannesburg, South Africa Mark Mirochnick - Boston Medical Centre, Boston, USA Lynne Mofenson - National Institute of Health, Rockville, USA Lulu Muhe - Child and Adolescent Health, WHO Secretariat HQ Veronica Mulega - Department of Paediatrics, Private Bag RW 1X Zambia Atieno Ojoo - UNICEF Copenhagen, Denmark Paul Palumbo - University of Dartmouth, USA Martina Penazzato - University of Padova, Italy Ryan Phelps - U.S. Agency for International Development, Washington DC, USA Eloan Pinheiro - Institute of Drug Technology, Brazil Jorge Pinto - Pederal University of Minas Gerais, Brazil Joann Schulte - Centre for Disease Control and Prevention, Atlanta USA Steven Spector - University of California San Diego, USA Nandita Sugandhi - Clinton Health Access Initiative, Boston USA
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