MOPE035 Poster Exhibition
Using WHO 2010 dosing guidelines, efavirenz levels remain slightly lower and highly variable in Ugandan/Zambian children weighing 10-< 20kg
Presented by Diana Gibb (United Kingdom).
Q. Fillekes1, E. Kaudha2, V. Korutaro3, C. Chabala4, M. Thomason5, V. Mulenga4, A. Kekitiinwa3, S. Walker5, D. Burger1, D. Gibb6
1Radboud University Nijmegen Medical Centre, Pharmacy, Nijmegen, Netherlands, 2JCRC, Paediatrics, Kampala, Uganda, 3Baylor Uganda PIDC, Kampala, Uganda, 4University Teaching Hospital, Lusaka, Zambia, 5MRC CTU, London, United Kingdom, 6MRC CTU, HIV Group, London, United Kingdom
Background: WHO updated guidelines for weight-band-based efavirenz-dosing in 2010, but these have not been evaluated in pharmacokinetic studies. New generic efavirenz tablets, scored once/twice on different sides to provide 200mg/300mg/400mg divided pill doses, also await evaluation.
Methods: Ugandan/Zambian children, weighing 10-< 20kg and taking generic double-scored efavirenz tablets plus combination tablets of lamivudine/abacavir or lamivudine/zidovudine were enrolled in a pharmacokinetic sub-study in the CHAPAS-3 trial. The once-daily efavirenz doses were 200mg and 300mg for those weighing 10-< 14kg and 14-< 20kg, respectively. Intensive pharmacokinetic plasma sampling (t=0,1,2,4,6,8,12,24 hours after observed intake) was performed 6 weeks after ART initiation. Area under the curve(AUC0-24h), maximum concentration(Cmax) and trough(C24h) levels were analysed.
Results: 31 Ugandan/Zambian children were enrolled and 29 efavirenz profiles (10-< 14kg weightbands(n=11), 14-< 20kg(n=18)) were evaluable. 17(57%) children were boys; median(interquartile range) age was 4.6(3.9-5.0) years. The geometric mean(95%CI) AUC0-24 was 46.5(29.4-73.6) and 49.7(30.9-79.9)h.mg/L for weight-band 10-< 14 and 14-< 20kg respectively, compared to 58h.mg/L in adults. There was no significant variation in any pharmacokinetic parameters between the weight-bands (rank-sum p>0.6). However, variability was high with CV% 133%, 104% and 156% for AUC0-24h,Cmax and C24h, respectively. 9%children weighing 10-< 14kg had a subtherapeutic C8h and/or C12h (< 1.0 mg/L) and 27% had a supratherapeutic C8h and/or C12h (>4.0 mg/L). 22% children weighing 14-< 20kg had a subtherapeutic C8h and/or C12h and 28% had a supratherapeutic C8h and/or C12h (exact p=0.87; Table).
[efavirenz PK levels at 8, 12 and 24h after intake]
|Hours after intake||Weight band||< 1.0 mg/L||1.0 - 4.0 mg/L||> 4.0 mg/L||Total number Children|
|8 and/or 12||10-<14 kg||1 (9%)||7 (64%)||3 (27%)||11|
| ||14-<20 kg||4 (22%)||9 (50%)||5 (28%)||18|
|24||10-<14 kg||6 (55%)||3 (27%)||2 (18%)||11|
| ||14-<20 kg||12 (67%)||2 (11%)||4 (22%)||18|
Conclusions: Efavirenz pharmacokinetic parameters in African children 10-< 20kg on daily efavirenz using 2010 WHO weight-bands and double-scored tablets, were more variable than data from adults, but similar to previously reported paediatric values, demonstrating the challenges of fixed-dosing when the therapeutic range is narrow. EFV toxicity and ART efficacy data collection is ongoing, alongside acceptability of the double-scored EFV tablet, which has potential to simplify delivery across age-bands from 3 years to adulthood.
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