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NP-003 Steady-state pharmacokinetics and early safety data in HIV-infected african children weighing ≥25 kg after switching to 50 mg film-coated dolutegravir tablets in the ODYSSEY trial
  1. PDJ Bollen1,
  2. A Turkova2,
  3. E Kaudha3,
  4. E Chidziva4,
  5. A Lugemwa5,
  6. A Kekitiinwa6,
  7. A Parker2,
  8. C Shakeshaft2,
  9. S Montero2,
  10. A Colbers1,
  11. A Nanduudu3,
  12. H Mujuru4,
  13. S Makumbi5,
  14. P Amuge6,
  15. P Rojo7,
  16. D Ford2,
  17. DM Burger1,
  18. DM Gibb2,
  19. The ODYSSEY trial team
  1. 1Department of Pharmacy and Radboud Institute for Health Sciences (RIHS), Radboud University Medical Center, Nijmegen, the Netherlands
  2. 2Medical Research Council Clinical Trials Unit at University College London, London, UK
  3. 3Joint Clinical Research Centre, Kampala, Uganda
  4. 4University of Zimbabwe Clinical Research Centre, Harare, Zimbabwe
  5. 5Joint Clinical Research Centre, Mbarara, Uganda
  6. 6Baylor College of Medicine, Kampala, Uganda
  7. 7Hospital 12 de Octubre, Madrid, Spain


Background and importance ODYSSEY is an ongoing international randomised trial evaluating dolutegravir (DTG)-based antiretroviral therapy (ART) versus standard-of-care in HIV-infected children starting first- or second-line ART. Pediatric DTG film-coated tablets (FCTs) of 10 mg and 25 mg are unavailable in low- and middle income countries (LMIC) were most HIV-infected children live. Adult DTG 50mg FTCs are produced by generic manufacturers at low-cost, are well-tolerated, and already available in many high- and LMICs.

Aim and objectives Within ODYSSEY pharmacokinetic (PK) substudies were undertaken to assess PK and safety data for a simplified paediatric DTG dosing approach using WHO weight bands (WBs) 25 to <30 kg and 30 to <40 kg and once daily 50 mg adult DTG doses.

Materials and methods Steady-state 24-hour PK curves were constructed from data in children (≥3 h fasted) observed taking current EMA-approved DTG doses of 25 mg and 35 mg (10 mg+25 mg FCTs)) in 25-<30 kg and 30-<40 kg WBs, respectively. After all children switched to single daily 50 mg DTG tablet, a second 24 h PK curve was constructed. We aimed to achieve DTG exposures comparable to historical adult data for DTG 50 mg FCTs QD taken under fasted conditions (geometric mean (GM): Ctrough0.83 mg/L, AUC0-24h43.4 h*mg/L, Cmax3.34 mg/L). Additionally, results were compared to PK data for DTG 50mg BID in adults (GM ranges: Ctrough2.41 to 2.72 mg/L, AUC0-24h93.4 to 92.7 h*mg/L, Cmax5.41 to 5.55 mg/L). Safety was evaluated after switch to the 50mg dose at 2, 4 and 12 weeks and then every 12 weeks.

Results 28 black-African children (52 PK profiles) from Uganda and Zimbabwe (61% male) with a median (range) age of 11.0(7.5–17.9) years old were included. For children weighing 25-<30 kg on DTG 25 mg (17 profiles) GM with coefficient of variation (CV%) for Ctrough and AUC0-24h was 0.39(48) mg/L and 33.1(23) h*mg/L, respectively, and after switch to DTG 50 mg (16 profiles) values were 0.77(43) mg/L and 58.6(28) h*mg/L, respectively. For children weighing 30-<40 kg on DTG 35 mg (9 profiles), Ctrough and AUC0-24h were 0.46(63) mg/L and 40.3(35) h*mg/L, and after switch to DTG 50 mg (10 profiles) values 0.63(49) mg/L and 53.5(32) h*mg/L, respectively. The 50 mg dose resulted in Cmax values of 5.41(25) mg/L and 5.22(25) mg/L in WB 25-<30 kg and 30-<40 kg, respectively, which did not exceed historical Cmax values for adults on 50 mg BID. After a median (IQR) follow-up of 30(12–30) weeks on 50 mg DTG 3/28(11%) children had grade 3 or 4 adverse events (one SAE; cryptococcal meningitis) and all were considered unrelated to DTG.

Conclusions and relevance Adult 50 mg FCT once-daily dolutegravir provides appropriate PK profiles in children ≥25 kg, with no safety signal, allowing practical dosing and rapid access to dolutegravir. WHO has released new pediatric dosing guidelines in response to these results.

  • Antiretroviral treatment
  • dolutegravir
  • pharmacokinetics
  • pediatrics.

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