PENTA 20 (Odyssey)

4

Dec, 2020

Pediatric dolutegravir (DTG) dosing recommendations derived from combined P1093 and ODYSSEY Population Pharmacokinetic analysis

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Authors: Singh R, Baker M, Thapar M, Gibb D, Turkova A, Ford D, Ruel T, Wiznia A, Farhad M, Alvero C, Green J, Bollen P, Colbers A, Burger D, Acosta E

Published in: 12th International Workshop on HIV Pediatrics

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Background: HIV treatment options remain limited in children. The recent Tivicay (dolutegravir, DTG) pediatric regulatory submissions propose WHO weight-band based recommendations for once-daily dosing in children ≥4 weeks of age using combined datasets from two pediatric studies: IMPAACT P1093 and ODYSSEY (PENTA20). These doses were informed by the Population PK (PopPK) analysis described below.

Methods: P1093 is a Phase I/II, non-comparative pharmacokinetic (PK) and safety study in HIV-1 infected children (≥4 weeks to <18 years of age). ODYSSEY is a non-inferiority, phase II/III study comparing the efficacy and toxicity of DTG plus 2 NRTIs vs. standard of care in infants and children. Intensive and sparse PK samples following dosing with film coated tablets (FCT), granules and dispersible tablet (DT) formulations in the fasted state and without regard to food were collected in P1093; intensive PK samples using FCTs and DTs in fasted state were collected in ODYSSEY. A PopPK model was developed with data from P1093 (1711 concentrations from n=151 participants) and ODYSSEY (939 concentrations from n=88 participants) to characterize PK, covariates, and associated variability. The final PopPK model simulated exposures across weight bands, doses, and formulations which were compared with established adult reference data.

Results: Of N=239 participants included, baseline age ranged from 0.17-17.5 years and weight from 3.9-91 kg, 50% were male and 80% were black. The model described study data and associated variability well with estimated mean (interindividual variability) CL/F=1.03L/h (29%) and V/F=13.6 L (107%). Based on observed and simulated data, dose stratification by age (<6 months and ≥6 months) in the 6 to <10 kg weight band (10 and 15 mg DTG DT, respectively) was proposed to account for metabolic enzyme maturation. The proposed doses are 5mg DT in 3 to <6kg; 10 mg DT in 6 to<10kg and <6 months, 15mg DT in 6 to <10kg and ≥6months, 20mg DT in 10 to <14kg, 25mg DT in 14 to <20kg and 30mg DT or 50 mg FCT in >20kg. At these doses, the simulated 24- hour concentration (C24h) was consistent across weight bands, similar to observed data, and met the minimum target concentrations of 0.697μg/mL. Similarly, simulated 24-hour area-under-the-curve (AUC24h) met the minimum target (46 h*μg/mL) across weight bands. Simulated maximum concentration (Cmax) results were 0.96 to 1.79- fold those observed historically in adults at the approved dose of DTG 50 mg BID (4.15 μg/mL). The safety exposure-response analysis demonstrated no relationships between PK parameters and adverse events.

Conclusions: Using FCT and DT formulations, DTG dosing in children ≥4 weeks of age on an age/weight-band basis provides comparable exposures to those historically observed in adults. Observed PK variability was higher in this pediatric population and no additional safety concerns were observed.

6

Aug, 2020

Simplified dolutegravir dosing for children with HIV weighing 20 kg or more: pharmacokinetic and safety substudies of the multicentre, randomised ODYSSEY trial

 

Authors: Bollen P,  Moore CL ,  Mujuru H et al; the ODYSSEY trial team

Published in: LANCET HIV. 2020;8:e533-e544

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.

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13

Mar, 2020

Adeqaute dolutegravir exposure dosed BID with rifampicin in children 6 to < 18 years

 

Authors: Waalewijn H, Mujuru HA, Amuge P, Cotton M, Bollen P, Chan M, Ali S, Variavan E, Makumbi S, Colbers A, Gibb D, Ford D, Burger D, Turkova A, and the ODYSSEY-trial team

Published in27th Conference on Retroviruses and Opportunistic Infections, March 8th –11th, 2020 – Boston.

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13

Mar, 2020

Adeqaute dolutegravir exposure dosed BID with rifampicin in children 6 to < 18 years

 

Authors: Waalewijn H, Mujuru HA, Amuge P, Cotton M, Bollen P, Chan M, Ali S, Variavan E,Makumbi S, Colbers A, Gibb D, Ford D, Burger D, Turkova A, and the ODYSSEY-trial team

Published in: Oral presentation at 27th Conference on Retroviruses and Opportunistic Infections, March 8th –11th, 2020 – Boston.

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14

Nov, 2019

Analysing small groups within clinical trials, while borrowing information from larger groups

 

Authors: Turner B, Ford D, Moore C, Gibb D, Turkova A,  White I, and ODYSSEY trial team

Published in: Oral Presentation atInternational Society for Clinical Biostatics; July 16th 2019

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14

Sep, 2019

Pharmacokinetics of dolutegravir 5mg dispersible tablets in children weighing 6 to <20kg dosed using WHO weight bands

 

Authors: Waalewijn H, Bollen PDJ, Moore C, Kekitiinwa A, et al. The ODYSSEY Trail Team

Published in: Oral Presentation at 10th IAS Conference, July, 21-24th 2019

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14

Apr, 2019

Adult dolutegravir 50mg film-coated tablets in children living with HIV weighing 20 to <25 kg

 

Authors: Bollen P, Turkova A, Mujuru H, et al. for the ODYSSEY Trial Team

Published in: 26th Conference on Retroviruses and Opportunistic Infections, March 4th – 7th, 2019– Seattle. P_830

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14

Oct, 2018

Steady-state pharmacokinetics and early safety data in HIV-infected African children weighing 14 to <25kg on film-coated dolutegravir 25mg tablets

 

Authors: Bollen P, Turkova A, Hilda Mujuru H, et al. The ODYSSEY Trial Team

Published in: 10th International Workshop on HIV Pediatrics, Amsterdam, 20-21st July 2018. Poster Number 22

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14

Oct, 2018

ODYSSEY: design, current status, and baseline characteristics

 

Authors: Moore CL,  Kekitinwa A, Kaudha E, et al; the ODYSSEY Trial Team

Published in: 10th International Workshop on HIV Pediatrics, Amsterdam, July 20-21st, 2018. Poster Number 34

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9

Oct, 2018

“I failed to take them as I should and now I’m scared”: how can we support adolescents’ adherence on second line HIV treatment

 

Authors: Bernays S, Namukwaya S, Mupambireyi Z, Nanduudu A, Mujuru H, Turkova A, Gibb DM, Seeley J, and the ODYSSEY Trial Team.

Published in: 10th International Workshop on HIV Pediatrics, Amsterdam, July 20-21st 2018. Poster number 117

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