IAS 2019 – Oral abstract on ODYSSEY PK study presented at conference in Mexico City

Jul 30, 2019

We are delighted to report that a late breaker oral presentation on the key PK substudy nested within the ODYSSEY trial was accepted and presented at the 10th IAS Conference on HIV Science (IAS 2019) in Mexico City on 21-24 July, 2019. The presentation was delivered by PhD student Hylke Waalewijn on behalf of David Burger’s research group at the Radboud Institute for Health Sciences in Nijmegen, The Netherlands. Hylke’s research focuses on the pharmacokinetics of antiretroviral drugs, specifically in HIV infected children. The IAS Conference is the world’s most influential meeting on HIV research and its applications. Gathering more than 5,000 participants from over 140 countries, IAS 2019 presented the most critical advances in basic, clinical and operational HIV research that moves science into policy and practice.

 

Abstract: 

 

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

Authors:  H. Waalewijn1, P.D.J. Bollen1, C. Moore2, A. Kekitiinwa3, P. Amuge3, H. Mujuru4, E. Chidziva4, V. Musiime5, E. Kaudha5, A. Lugemwa6, S. Makumbi6, A. Violari7, E. Variava8, S. Ali2, C. Giaquinto9, P. Rojo10, A. Colbers1, D. Gibb2, D. Ford2, A. Turkova2, D. Burger1, and the ODYSSEY trial team
1Radboud University Medical Center /Radboud Institute for Health Sciences, Pharmacy, Nijmegen, Netherlands, 2University College London, Medical Research Council Clinical Trials Unit, London, United Kingdom, 3Baylor College of Medicine, Kampala, Uganda, 4University of Zimbabwe Clinical Research Centre, Harare, Zimbabwe, 5Joint Clinical Research Centre, Kampala, Uganda, 6Joint Clinical Research Centre, Mbarara, Uganda, 7Klerksdorp-Tsepong Hospital Complex, Matlosana, South Africa, 8Chris Hani Baragwanath Hospital, Perinatal HIV Research Unit (PHRU), Soweto, South Africa, 9University of Padova, Padova, Italy, 10Hospital 12 de Octubre, Madrid, Spain

 

Background

Dolutegravir (DTG) 5mg dispersible tablets (DT) are small, child-friendly and allow easy scaling. We describe a pharmacokinetic (PK) substudy of DTG 5mg DT in  children weighing 6-<20kg dosed by WHO weight bands conducted within ODYSSEY, an ongoing phase-III trial of DTG-based first- and second-line antiretroviral therapy (NCT02259127).

Methods

Children weighing 6-<10kg, 10-<14kg, 14-<20kg received DTG 5mg DT at 15, 20, and 25mg QD, respectively. At steady-state, 24-hour PK profiles (7 samples) were constructed  following observed intake of DTG. DTG plasma concentrations were measured using a validated UPLC-MS/MS method; Phoenix 64 was used for non-compartmental analysis. Results were compared to historical PK parameters from adults taking 50mg DTG film-coated tablets (FCT) QD or BID, previous ODYSSEY PK data and published data on DT from IMPAACT1093.

Results

28 children [29 PK curves] were included in the analysis from Zimbabwe and Uganda. PK results  (table 1) from weight bands 10-<14kg and 14-<20kg were similar to PK data from children receiving same DT doses in IMPAACT1093 and GM Ctrough values were similar to children 20-<40kg in ODYSSEY on DTG FCT 50mg and adults  on 50mg DTG FCT QD (0.83 mg/L). In children 14-<20kg, exposures were ~1.8-2-fold higher on 25mg DT than on 25mg FCT, similar to the bioavailability of DT/FCT in adults.Our data from the 6-<10kg weightband showed lower GM exposure to DTG compared to IMPAACT1093 with high variability and 3 of 8 children had observed Ctroughbelow EC90(0.32mg/L).

Conclusion

DTG DT in children weighing 10-<20kg, dosed QD in WHO weight bands achieves similar Ctroughto adults and older children on the adult DTG dose and young children on DT in IMPAACT1093. Some children in the 6-<10kg weight band had Ctroughlevels below EC90, and PK profiles showed high variability in this weight band. Further PK data collection in children 3-<10kg are ongoing and all children are being followed up for safety.

Odyssey Lower weightband PK substudies Reference adults
WHO weightband 6-<10kg 10-<14kg 14-<20kg ≥ 40kg/50mg FCT ≥ 40kg/50mg FCT BID
DTG dose and (N) 15mg DT (8) 20mg DT (8) 25mg DT (13) 50mg FCT (10a) 50mg FCT BID (12b; 24c)
Sex male, n (%) 1 (13%) 1 (13%) 7 (54%) 10 (100%) 10 (83%)b; 18 (75%)c
Age (years) 1.3 (0.6-3.0) 3.0 (1.6-4.2) 6.0(4.9-8.5) 34 (22-53) 48 (31-59)b; 47 (33-68)c
Weight (kg) 7.6 (6.7-9.7) 11.5 (10.0-12.6) 18.0 (14.9-19.9)
Dose/weight (mg/kg) 2.0 (1.5-2.2) 1.7 (1.6-2.0) 1.4 (1.3-1.7)
Ctrough(mg/L); %below EC90 0.43 (207); 37.5% 0.77 (62); 0% 0.85 (67); 0% 0.83 (26)a 2.41 (77)b; 2.72 (70)c
AUC0-24h(mg*h/L) 46.3 (90) 76.0 (25) 69.6 (30) 43.4 (20)a 92.7 (55)b; 93.4 (50)c
Cmax(mg/L) 5.3 (58) 8.0 (25) 7.1 (21) 3.3 (16)a 5.6 (49)b; 5.4 (40)c
Pharmacokinetic parameters are expressed as geometric mean with coefficient of variation (%), median (range) for age, weight and dose/weight. Doses represent once daily doses, unless otherwise specified. FCT, film-coated tablet; DT, dispersible tablet; BID, twice daily. aFasted HIV-positive adults. bFasted healthy HIV-negative adults. cHIV-positive treatment experienced adults, fed state not specified.

 

  • Read the full presentation here.
  • Video link to the presentation here.