- Email: [email protected]
Improved labelling of antiretrovirals for paediatric use
Comment
Improved labelling of antiretrovirals for paediatric use Published Online October 17, 2016 http://dx.doi.org/10.1016/ S2352-3018(16)30175-8 See Articles page e561
See Online for appendix
“Children are not just small adults” has been the mantra of paediatric pharmacology for decades. It reflects that a drug’s pharmacokinetic and pharmacodynamic properties cannot directly be extrapolated from adults to children. For many drugs, data regarding their use in children are scarce or unavailable, an d if these drugs are used in children it is often off-label and on the basis of little evidence. Labelling of drugs for paediatric use has changed substantially after authorisation of the Best Pharmaceuticals for Children Act in the USA in 2002 and paediatric medicines regulation in the European Union in 2007. Since then, significant progress has been made in the field of paediatric medicines, but is enough being done?1 For antiretrovirals, there is often a lag time of 4 years or more between the registration for their use in adults and registration for their use in children and adolescents (table). The US Department of Human Health Services for the use of antiretrovirals in adults and children was updated in 2016 (appendix).2,3 Remarkably, the two guidelines show little concordance, and only a raltegravir-based regimen is listed in both. A major difference is in the so-called third drug mentioned in both guidelines: novel drugs such as dolutegravir and elvitegravir are already recommended for adults and adolescents, whereas older drugs such as ritonavir-boosted lopinavir and efavirenz are still preferred in children younger than 12 years. An enormous and unacceptable delay exists in acquiring pharmacokinetic and pharmacodynamic data in the youngest groups, which often have unmet medical needs. For example, with early infant diagnosis of HIV and early treatment being Adult approval
Paediatric approval (aged Current indications <12 years)
Atazanavir
June, 2003
June, 2014
Darunavir
June, 2006
Dec, 2011
>5 kg and >3 months >10 kg and >3 years
Etravirine
Jan, 2008
March, 2012
Rilpivirine
May, 2011
··
>6 years
Raltegravir
Oct, 2007
Dec, 2011, and Dec, 2013
Elvitegravir (as part of Stribild)
Aug, 2012
··
>18 years
Elvitegravir (as part of Genvoya)
Nov, 2015
··
>12 years
Dolutegravir
Aug, 2013
··
>12 years
>18 years >4 weeks
*Based on data from www.FDA.gov (accessed Aug 29, 2016). ··=not applicable.
Table: Dates of recent adult and paediatric approvals of relevant antiretrovirals by the US Food and Drug Agency*
e550
promoted as a possibility for cure, we need more approved antiretrovirals for newborn babies than we have. Additionally, the necessity of separate studies in adolescents is doubtful, when data from adults are already available. From a pharmacokinetic perspective, adolescents are similar to adults; eg, no single antiretroviral drug needs to be dosed differently in children weighing more than 35 kg versus adults. In The Lancet HIV, Aditya Gaur and colleagues4 present the results of their 48-week, single-arm, open-label study of a fixed-dose combination tablet containing 150 mg elvitegravir, 150 mg cobicistat, 200 mg emtricitabine, and 10 mg tenofovir alafenamide given to 50 treatmentnaive HIV-infected adolescents aged 12–18 years. This non-comparative study was needed to acquire regulatory approval for use in adolescents but used the same dose and formulation as already approved in adults. The primary objectives were pharmacokinetic parameters and safety. Clinical pharmacology principles state that once pharmacokinetics are similar between subgroups, safety and efficacy should also be similar. But when comparing adults with children, this might not always be the case because children could be more sensitive to drug effects. The prodrug tenofovir alafenamide has been developed to achieve a more favourable intracellular to plasma ratio of tenofovir than obtained with tenofovir disoproxil fumarate, if this observation was repeated in adolescents, there should arguably be no concern about tenofovir toxicity5,6 in this subgroup of patients. As a consequence, a small pharmacokinetic study could have been sufficient to show similar exposure and enough for regulatory approval, saving time and resources. If concerns still lingered regarding renal and bone toxicity from tenofovir alafenamide in adolescents, a much larger study than Gaur and colleagues’ study should be done. The nucleoside/nucleotide reverse transcriptase inhibitor (NRTI) backbone in the preferred regimens remarkably differs between children and adults (appendix). This difference probably reflects concerns around bone toxicity of tenofovir disoproxil fumarate that restricts its use in children younger than 12 years. As a consequence zidovudine is still listed as a preferred NRTI although its use in adults was abandoned several years ago. The paediatric development of tenofovir alafenamide will hopefully change this situation soon, although this www.thelancet.com/hiv Vol 3 December 2016
Comment
should have happened much earlier after the selective intracellular activation of tenofovir alafenamide was discovered in 2005.7 For children especially, tenofovir alafenamide was a much more attractive antiretroviral option than tenofovir disoproxil fumarate, so why was this prodrug not developed for children who are potentially more sensitive to the renal and bone toxicity caused by tenofovir disoproxil fumarate ? In conclusion, we are happy with the improved knowledge of the pharmacokinetics and pharmacodynamics of antiretrovirals in children, and that almost all new antiretrovirals now have paediatric approvals. But these developments should be prioritised, serving subgroups of patients with the highest needs, and with the promise of treating children as well as we do adults.
University Medical Center Rotterdam, Netherlands (AMCvR) [email protected] We declare no competing interests. 1 2
3
4
5
6
*David M Burger, Annemarie M C van Rossum Department of Pharmacy & Radboud Institute for Health Sciences, Radboud University Medical Center, 6525 GA, Nijmegen, Netherlands (DMB); and Department of Paediatrics, Division of Pediatric Infectious Diseases and Immunology, Erasmus MC
7
Ito S. Children: are we doing enough? Clin Pharmacol Ther 2015; 98: 222–24. US Department of Health and Human Services. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. July 14, 2016. https://aidsinfo.nih.gov/contentfiles/lvguidelines/ adultandadolescentgl.pdf (accessed Aug 29, 2016). Panel on antiretroviral therapy and medical management of HIV-infected children. Guidelines for the use of antiretroviral agents in pediatric HIV infection. March 1, 2016. http://aidsinfo.nih.gov/contentfiles/lvguidelines/ pediatricguidelines.pdf (accessed Aug 29 2016). Gaur AH, Kizito H, Prasitsueubsai W. Safety, efficacy, and pharmacokinetics of a single-tablet regimen containing elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide in treatment-naive, HIV-infected adolescents: a single-arm, open-label trial. Lancet HIV 2016; published Oct 17. http://dx.doi.org/10.1016/S2352-3018(16)30121-7. Ezinga M, Wetzels JF, Bosch ME, van der Ven AJ, Burger DM. Long-term treatment with tenofovir: prevalence of kidney tubular dysfunction and its association with tenofovir plasma concentration. Antivir Ther 2014; 19: 765–71. Okonkwo RI, Weidmann AE, Effa EE. Renal and bone adverse effects of a tenofovir-based regimen in the treatment of HIV-infected children: a systematic review. Drug Saf 2016; 39: 209–18. Lee WA, He GX, Eisenberg E, et al. Selective intracellular activation of a novel prodrug of the human immunodeficiency virus reverse transcriptase inhibitor tenofovir leads to preferential distribution and accumulation in lymphatic tissue. Antimicrob Agents Chemother 2005; 49: 1898–906.
When is a PrEP candidate ready for phase 3? Long-acting products for HIV pre-exposure prophylaxis (PrEP) are in development to reduce the daily burden of oral drugs. Long-acting alternatives include monthly intravaginal rings proven for prevention (dapivirine), bimonthly implantable drugs proven for treatment (cabotegravir and rilpivirine), and possibly yearly implantable devices still in preclinical development. In The Lancet HIV, Ian McGowan and colleagues contribute substantially to progress with long-acting rilpivirine,1 highlighting the benefits, limitations, and puzzles of long-acting PrEP development. How should one apply their new data to inform the efficient advancement of long-acting rilpivirine PrEP development? If a product proves effective for treatment, are any pharmacokinetic data needed to advance to PrEP trials? Oral tenofovir disoproxil fumarate and emtricitabine are dosed the same for PrEP as for treatment, although not in combination with other potent treatment drugs. McGowan and colleagues noted concerns with the concentration of rilpivirine in cervicovaginal tissue, which reached only two-thirds of the amount in plasma. However, long-acting cabotegravir achieves concentrations in rectal tissue that are only 6% of those in plasma, www.thelancet.com/hiv Vol 3 December 2016
and levels in cervicovaginal tissue are only 16–19% of those in plasma; yet, cabotegravir is entering clinical trials for comparison with daily oral tenofovir disoproxil fumarate and emtricitabine.2 Transmission-relevant compartmental pharmacokinetic studies of rilpivirine and cabotegravir inform PrEP management by answering questions such as “How long before the injection protects?” and “If I want to stop using injectable drugs for PrEP, for how long do I take oral PrEP to avoid resistant HIV infection?” Rilpivirineresistant HIV seroconversion has been reported many months after cessation of long-acting rilpivirine,3 which was attributed to the long rilpivirine concentration tail. Which protection biomarker provides evidence to advance to efficacy testing? The inability in phase 2 studies to assess clinical antiretroviral concentration-response directly, to guide dose-selection for phase 3, requires use of imperfect biomarkers of protective antiretroviral effect. Accordingly, the most concerning finding in the report by McGowan and colleagues is the failure to show longacting rilpivirine protection in the cervicovaginal explant model, particularly when contrasted with rectal explant protection.1 Ex vivo HIV challenge has shown antiviral protection after clinical dosing of several antiretroviral
Published Online September 15, 2016 http://dx.doi.org/10.1016/ S2352-3018(16)30162-X See Articles page e569
e551
Improved labelling of antiretrovirals for paediatric use Published Online October 17, 2016 http://dx.doi.org/10.1016/ S2352-3018(16)30175-8 See Articles page e561
See Online for appendix
“Children are not just small adults” has been the mantra of paediatric pharmacology for decades. It reflects that a drug’s pharmacokinetic and pharmacodynamic properties cannot directly be extrapolated from adults to children. For many drugs, data regarding their use in children are scarce or unavailable, an d if these drugs are used in children it is often off-label and on the basis of little evidence. Labelling of drugs for paediatric use has changed substantially after authorisation of the Best Pharmaceuticals for Children Act in the USA in 2002 and paediatric medicines regulation in the European Union in 2007. Since then, significant progress has been made in the field of paediatric medicines, but is enough being done?1 For antiretrovirals, there is often a lag time of 4 years or more between the registration for their use in adults and registration for their use in children and adolescents (table). The US Department of Human Health Services for the use of antiretrovirals in adults and children was updated in 2016 (appendix).2,3 Remarkably, the two guidelines show little concordance, and only a raltegravir-based regimen is listed in both. A major difference is in the so-called third drug mentioned in both guidelines: novel drugs such as dolutegravir and elvitegravir are already recommended for adults and adolescents, whereas older drugs such as ritonavir-boosted lopinavir and efavirenz are still preferred in children younger than 12 years. An enormous and unacceptable delay exists in acquiring pharmacokinetic and pharmacodynamic data in the youngest groups, which often have unmet medical needs. For example, with early infant diagnosis of HIV and early treatment being Adult approval
Paediatric approval (aged Current indications <12 years)
Atazanavir
June, 2003
June, 2014
Darunavir
June, 2006
Dec, 2011
>5 kg and >3 months >10 kg and >3 years
Etravirine
Jan, 2008
March, 2012
Rilpivirine
May, 2011
··
>6 years
Raltegravir
Oct, 2007
Dec, 2011, and Dec, 2013
Elvitegravir (as part of Stribild)
Aug, 2012
··
>18 years
Elvitegravir (as part of Genvoya)
Nov, 2015
··
>12 years
Dolutegravir
Aug, 2013
··
>12 years
>18 years >4 weeks
*Based on data from www.FDA.gov (accessed Aug 29, 2016). ··=not applicable.
Table: Dates of recent adult and paediatric approvals of relevant antiretrovirals by the US Food and Drug Agency*
e550
promoted as a possibility for cure, we need more approved antiretrovirals for newborn babies than we have. Additionally, the necessity of separate studies in adolescents is doubtful, when data from adults are already available. From a pharmacokinetic perspective, adolescents are similar to adults; eg, no single antiretroviral drug needs to be dosed differently in children weighing more than 35 kg versus adults. In The Lancet HIV, Aditya Gaur and colleagues4 present the results of their 48-week, single-arm, open-label study of a fixed-dose combination tablet containing 150 mg elvitegravir, 150 mg cobicistat, 200 mg emtricitabine, and 10 mg tenofovir alafenamide given to 50 treatmentnaive HIV-infected adolescents aged 12–18 years. This non-comparative study was needed to acquire regulatory approval for use in adolescents but used the same dose and formulation as already approved in adults. The primary objectives were pharmacokinetic parameters and safety. Clinical pharmacology principles state that once pharmacokinetics are similar between subgroups, safety and efficacy should also be similar. But when comparing adults with children, this might not always be the case because children could be more sensitive to drug effects. The prodrug tenofovir alafenamide has been developed to achieve a more favourable intracellular to plasma ratio of tenofovir than obtained with tenofovir disoproxil fumarate, if this observation was repeated in adolescents, there should arguably be no concern about tenofovir toxicity5,6 in this subgroup of patients. As a consequence, a small pharmacokinetic study could have been sufficient to show similar exposure and enough for regulatory approval, saving time and resources. If concerns still lingered regarding renal and bone toxicity from tenofovir alafenamide in adolescents, a much larger study than Gaur and colleagues’ study should be done. The nucleoside/nucleotide reverse transcriptase inhibitor (NRTI) backbone in the preferred regimens remarkably differs between children and adults (appendix). This difference probably reflects concerns around bone toxicity of tenofovir disoproxil fumarate that restricts its use in children younger than 12 years. As a consequence zidovudine is still listed as a preferred NRTI although its use in adults was abandoned several years ago. The paediatric development of tenofovir alafenamide will hopefully change this situation soon, although this www.thelancet.com/hiv Vol 3 December 2016
Comment
should have happened much earlier after the selective intracellular activation of tenofovir alafenamide was discovered in 2005.7 For children especially, tenofovir alafenamide was a much more attractive antiretroviral option than tenofovir disoproxil fumarate, so why was this prodrug not developed for children who are potentially more sensitive to the renal and bone toxicity caused by tenofovir disoproxil fumarate ? In conclusion, we are happy with the improved knowledge of the pharmacokinetics and pharmacodynamics of antiretrovirals in children, and that almost all new antiretrovirals now have paediatric approvals. But these developments should be prioritised, serving subgroups of patients with the highest needs, and with the promise of treating children as well as we do adults.
University Medical Center Rotterdam, Netherlands (AMCvR) [email protected] We declare no competing interests. 1 2
3
4
5
6
*David M Burger, Annemarie M C van Rossum Department of Pharmacy & Radboud Institute for Health Sciences, Radboud University Medical Center, 6525 GA, Nijmegen, Netherlands (DMB); and Department of Paediatrics, Division of Pediatric Infectious Diseases and Immunology, Erasmus MC
7
Ito S. Children: are we doing enough? Clin Pharmacol Ther 2015; 98: 222–24. US Department of Health and Human Services. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. July 14, 2016. https://aidsinfo.nih.gov/contentfiles/lvguidelines/ adultandadolescentgl.pdf (accessed Aug 29, 2016). Panel on antiretroviral therapy and medical management of HIV-infected children. Guidelines for the use of antiretroviral agents in pediatric HIV infection. March 1, 2016. http://aidsinfo.nih.gov/contentfiles/lvguidelines/ pediatricguidelines.pdf (accessed Aug 29 2016). Gaur AH, Kizito H, Prasitsueubsai W. Safety, efficacy, and pharmacokinetics of a single-tablet regimen containing elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide in treatment-naive, HIV-infected adolescents: a single-arm, open-label trial. Lancet HIV 2016; published Oct 17. http://dx.doi.org/10.1016/S2352-3018(16)30121-7. Ezinga M, Wetzels JF, Bosch ME, van der Ven AJ, Burger DM. Long-term treatment with tenofovir: prevalence of kidney tubular dysfunction and its association with tenofovir plasma concentration. Antivir Ther 2014; 19: 765–71. Okonkwo RI, Weidmann AE, Effa EE. Renal and bone adverse effects of a tenofovir-based regimen in the treatment of HIV-infected children: a systematic review. Drug Saf 2016; 39: 209–18. Lee WA, He GX, Eisenberg E, et al. Selective intracellular activation of a novel prodrug of the human immunodeficiency virus reverse transcriptase inhibitor tenofovir leads to preferential distribution and accumulation in lymphatic tissue. Antimicrob Agents Chemother 2005; 49: 1898–906.
When is a PrEP candidate ready for phase 3? Long-acting products for HIV pre-exposure prophylaxis (PrEP) are in development to reduce the daily burden of oral drugs. Long-acting alternatives include monthly intravaginal rings proven for prevention (dapivirine), bimonthly implantable drugs proven for treatment (cabotegravir and rilpivirine), and possibly yearly implantable devices still in preclinical development. In The Lancet HIV, Ian McGowan and colleagues contribute substantially to progress with long-acting rilpivirine,1 highlighting the benefits, limitations, and puzzles of long-acting PrEP development. How should one apply their new data to inform the efficient advancement of long-acting rilpivirine PrEP development? If a product proves effective for treatment, are any pharmacokinetic data needed to advance to PrEP trials? Oral tenofovir disoproxil fumarate and emtricitabine are dosed the same for PrEP as for treatment, although not in combination with other potent treatment drugs. McGowan and colleagues noted concerns with the concentration of rilpivirine in cervicovaginal tissue, which reached only two-thirds of the amount in plasma. However, long-acting cabotegravir achieves concentrations in rectal tissue that are only 6% of those in plasma, www.thelancet.com/hiv Vol 3 December 2016
and levels in cervicovaginal tissue are only 16–19% of those in plasma; yet, cabotegravir is entering clinical trials for comparison with daily oral tenofovir disoproxil fumarate and emtricitabine.2 Transmission-relevant compartmental pharmacokinetic studies of rilpivirine and cabotegravir inform PrEP management by answering questions such as “How long before the injection protects?” and “If I want to stop using injectable drugs for PrEP, for how long do I take oral PrEP to avoid resistant HIV infection?” Rilpivirineresistant HIV seroconversion has been reported many months after cessation of long-acting rilpivirine,3 which was attributed to the long rilpivirine concentration tail. Which protection biomarker provides evidence to advance to efficacy testing? The inability in phase 2 studies to assess clinical antiretroviral concentration-response directly, to guide dose-selection for phase 3, requires use of imperfect biomarkers of protective antiretroviral effect. Accordingly, the most concerning finding in the report by McGowan and colleagues is the failure to show longacting rilpivirine protection in the cervicovaginal explant model, particularly when contrasted with rectal explant protection.1 Ex vivo HIV challenge has shown antiviral protection after clinical dosing of several antiretroviral
Published Online September 15, 2016 http://dx.doi.org/10.1016/ S2352-3018(16)30162-X See Articles page e569
e551