Simplified dolutegravir dosing for children with HIV weighing 20 kg or more: pharmacokinetic and safety substudies of the multicentre, randomised ODYSSEY trial
Pauline D J Bollen, Cecilia L Moore, Hilda A Mujuru, Shafic Makumbi, Adeodata R Kekitiinwa, Elisabeth Kaudha, Anna Parker, Godfrey Musoro, Annet Nanduudu, Abbas Lugemwa, Pauline Amuge, James G Hakim, Pablo Rojo, Carlo Giaquinto, Angela Colbers, Diana M Gibb, Deborah Ford, Anna Turkova, David M Burger, ODYSSEY trial team, Pauline D J Bollen, Cecilia L Moore, Hilda A Mujuru, Shafic Makumbi, Adeodata R Kekitiinwa, Elisabeth Kaudha, Anna Parker, Godfrey Musoro, Annet Nanduudu, Abbas Lugemwa, Pauline Amuge, James G Hakim, Pablo Rojo, Carlo Giaquinto, Angela Colbers, Diana M Gibb, Deborah Ford, Anna Turkova, David M Burger, ODYSSEY trial team
Abstract
Background: Paediatric dolutegravir doses approved by stringent regulatory authorities (SRAs) for children weighing 20 kg to less than 40 kg until recently required 25 mg and 10 mg film-coated tablets. These tablets are not readily available in low-resource settings where the burden of HIV is highest. We did nested pharmacokinetic substudies in patients enrolled in the ODYSSEY-trial to evaluate simplified dosing in children with HIV.
Methods: We did pharmacokinetic and safety substudies within the open-label, multicentre, randomised ODYSSEY trial (NCT02259127) of children with HIV starting treatment in four research centres in Uganda and Zimbabwe. Eligible children were randomised to dolutegravir in ODYSSEY and weighed 20 kg to less than 40 kg. In children weighing 20 kg to less than 25 kg, we assessed dolutegravir's pharmacokinetics in children given once daily 25 mg film-coated tablets (approved by the SRAs at the time of the study) in part one of the study, and 50 mg film-coated tablets (adult dose) or 30 mg dispersible tablets in part two of the study. In children weighing 25 kg to less than 40 kg, we also assessed dolutegravir pharmacokinetics within-subject on film-coated tablet doses of 25 mg or 35 mg once daily, which were approved by the SRAs for the children's weight band; then switched to 50 mg film-coated tablets once daily. Steady-state 24 h dolutegravir plasma concentration-time pharmacokinetic profiling was done in all enrolled children at baseline and 1, 2, 3, 4, 6, and 24 h after observed dolutegravir intake. Target dolutegravir trough concentrations (Ctrough) were based on reference adult pharmacokinetic data and safety was evaluated in all children in the corresponding weight bands who consented to pharmacokinetic studies and received the studied doses.
Findings: Between Sept 22, 2016, and May 31, 2018, we enrolled 62 black-African children aged from 6 years to younger than 18 years (84 pharmacokinetic-profiles). In children weighing 20 kg to less than 25 kg taking 25 mg film-coated tablets, the geometric mean (GM) Ctrough (coefficient of variation) was 0·32 mg/L (94%), which was 61% lower than the GM Ctrough of 0·83 mg/L (26%) in fasted adults on dolutegravir 50 mg once-daily; in children weighing 25 kg to less than 30 kg taking 25 mg film-coated tablets, the GM Ctrough was 0·39 mg/L (48%), which was 54% lower than the GM Ctrough in fasted adults; and in those 30 kg to less than 40 kg taking 35 mg film-coated tablets the GM Ctrough was 0·46 mg/L (63%), which was 45% lower than the GM Ctrough in fasted adults. On 50 mg film-coated tablets or 30 mg dispersible tablets, Ctrough was close to the adult reference (with similar estimates on the two formulations in children in the 20 to <25 kg weight band), with total exposure (area under the concentration-time curve from 0 h to 24 h) in between reference values in adults dosed once and twice daily, where safety data are reassuring, although maximum concentrations were higher in children weighing 20 kg to less than 25 kg than in the twice-daily adult reference. Over a 24-week follow-up period in 47 children on 30 mg dispersible tablets or 50 mg film-coated tablets, none of the three reported adverse events (cryptococcal meningitis, asymptomatic anaemia, and asymptomatic neutropenia) were considered related to dolutegravir.
Interpretation: Adult dolutegravir 50 mg film-coated tablets given once daily provide appropriate pharmacokinetic profiles in children weighing 20 kg or more, with no safety signal, allowing simplified practical dosing and rapid access to dolutegravir. These results informed the WHO 2019 dolutegravir paediatric dosing guidelines and have led to US Food and Drug Administration approval of adult dosing down to 20 kg.
Funding: Paediatric European Network for Treatment of AIDS Foundation, ViiV Healthcare, UK Medical Research Council.
Copyright © 2020 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.
Figures
References
- UNAIDS Core epidemiology slides. 2019.
- Hamers RL, Rinke de Wit TF, Holmes CB. HIV drug resistance in low-income and middle-income countries. Lancet HIV. 2018;5:e588–e596.
- UNAIDS Start free Stay free AIDS free, 2019 report. 2019.
- WHO Updated recommendations on first-line and second-line antiretroviral regimens and post-exposure prophylaxis and recommendations on early infant diagnosis of HIV: interim guidelines. December, 2018. (July 28, 2019).
- Clinton Health Access Initiative 2018 HIV market report: the state of the HIV treatment, testing, and prevention markets in low- and middle-income countries. 2017–2022.
- Cahn P, Pozniak AL, Mingrone H. Dolutegravir versus raltegravir in antiretroviral-experienced, integrase-inhibitor-naive adults with HIV: week 48 results from the randomised, double-blind, non-inferiority SAILING study. Lancet. 2013;382:700–708.
- Penazzato M, Watkins M, Morin S. Catalysing the development and introduction of paediatric drug formulations for children living with HIV: a new global collaborative framework for action. Lancet HIV. 2018;5:e259–e264.
- Viani RM, Alvero C, Fenton T. Safety, pharmacokinetics and efficacy of dolutegravir in treatment-experienced HIV-1 infected adolescents: forty-eight-week results from IMPAACT P1093. Pediatr Infect Dis J. 2015;34:1207–1213.
- Viani RM, Ruel T, Alvero C. Long-term safety and efficacy of dolutegravir in treatment-experienced adolescents with human immunodeficiency virus infection: results of the IMPAACT P1093 study. J Pediatric Infect Dis Soc. 2020;9:159–165.
- Tivicay EMA. Summary of product characteristics. May 21, 2019.
- US Food and Drug Administration Prescribing information tivicay. October, 2014.
- Hwang B, Shroufi A, Gils T. Stock-outs of antiretroviral and tuberculosis medicines in South Africa: a national cross-sectional survey. PLoS One. 2019;14
- WHO Annex 3. Dosages of ARV drugs for adults and adolescents. Annex to interim guidelines; updated recommendations on first-line and second-line antiretroviral regimens and post-exposure prophylaxis and recommendations on early infant diagnosis of HIV. 2018.
- Ruel TA, Singh EP, Alvero RP, et al. PK and 4-week outcomes of dolutegravir dispersible tablets in HIV-infected children. Retroviruses and Opportunistic Infections (CROI); Seattle, WA, USA; March 4–7, 2019 (abstr 829).
- Mukui IRB, Mwalili S, Bukusi E, Farquhar C. High prescription error rates amoung children on antiretroviral therapy in Kenya. Retroviruses and Opportunistic Infections (CROI); Seattle, WA, USA; March 4–7, 2019 (poster 824).
- Buchanan A AK, Singh R, Parasrampuria R, Barthel S, Orr B, Wolstenholme A, DiLullo K. Clinical pharmacology study report 205893: a 2-part, phase I, single dose, crossover relative bioavailability study of both TIVICAY 10 mg conventional tablets and 5 mg dispersible tablets compared with conventional tivicay tablets in healthy adult subjects: VIIV healthcare and the glaxosmithkline group of companies. 2017.
- Wang Y, Jadhav PR, Lala M, Gobburu JV. Clarification on precision criteria to derive sample size when designing pediatric pharmacokinetic studies. J Clin Pharmacol. 2012;52:1601–1606.
- Bollen PDJ, de Graaff-Teulen MJA, Schalkwijk S, van Erp NP, Burger DM. Development and validation of an UPLC-MS/MS bioanalytical method for simultaneous quantification of the antiretroviral drugs dolutegravir, elvitegravir, raltegravir, nevirapine and etravirine in human plasma. J Chromatogr B Analyt Technol Biomed Life Sci. 2019;1105:76–84.
- Min S, Sloan L, DeJesus E. Antiviral activity, safety, and pharmacokinetics/pharmacodynamics of dolutegravir as 10-day monotherapy in HIV-1-infected adults. AIDS. 2011;25:1737–1745.
- Eron JJ, Clotet B, Durant J. Safety and efficacy of dolutegravir in treatment-experienced subjects with raltegravir-resistant HIV type 1 infection: 24-week results of the VIKING Study. J Infect Dis. 2013;207:740–748.
- A pilot study assessing the integrase inhibitor GSK1349572 in HIV-infected persons with virus resistant to raltegravir. Study results. 2013.
- US Food and Drug administration Clinical pharmacology and biopharmaceutics review. Dolutegravir (Tivicay) 2013.
- Williams RL, Chen ML, Hauck WW. Equivalence approaches. Clin Pharmacol Ther. 2002;72:229–237.
- US Food and Drug administration Clinical review. Dolutegravir sNDA 204790 (Tivicay) 2016.
- Kobayashi M, Yoshinaga T, Seki T. In vitro antiretroviral properties of S/GSK1349572, a next-generation HIV integrase inhibitor. Antimicrob Agents Chemother. 2011;55:813–821.
- van Lunzen J, Maggiolo F, Arribas JR. Once daily dolutegravir (S/GSK1349572) in combination therapy in antiretroviral-naive adults with HIV: planned interim 48 week results from SPRING-1, a dose-ranging, randomised, phase 2b trial. Lancet Infect Dis. 2012;12:111–118.
- Anderson BJ, Holford NH. Understanding dosing: children are small adults, neonates are immature children. Arch Dis Child. 2013;98:737–744.
- Song I, Borland J, Chen S. Effect of food on the pharmacokinetics of the integrase inhibitor dolutegravir. Antimicrob Agents Chemother. 2012;56:1627–1629.
- Elliot ER, Wang X, Singh S. Increased dolutegravir peak concentrations in people living with human immunodeficiency virus aged 60 and over, and analysis of sleep quality and cognition. Clin Infect Dis. 2019;68:87–95.
- US Food and Drug Administration Prescribing information descovy. April, 2017.
- Natukunda E, Gaur AH, Kosalaraksa P. Safety, efficacy, and pharmacokinetics of single-tablet elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide in virologically suppressed, HIV-infected children: a single-arm, open-label trial. Lancet Child Adolesc Health. 2017;1:27–34.
- US Food and Drug Administration Prescribing information epzicom. March, 2017.
- Mylan Mylan receives tentative approval for combination HIV treatment DTG/FTC/TAF under FDA's PEPFAR program. Feb 20, 2018.
- US Food and Drug Administration Highlights of prescribing information. Tivicay. June, 2020.
Source: PubMed