Abacavir pharmacokinetics in African children living with HIV: A pooled analysis describing the effects of age, malnutrition and common concomitant medications. Issue 2 (12th August 2021)

• Record Type: Journal Article
• Authors: Tikiso, Tjokosela; McIlleron, Helen; Burger, David; Gibb, Diana; Rabie, Helena; Lee, Janice; Lallemant, Marc; Cotton, Mark F.; Archary, Moherndran; Hennig, Stefanie; Denti, Paolo
• Is Part Of: British journal of clinical pharmacology. Volume 88:Issue 2(2022)
• Page Start: 403
• Page End: 415
• Publication Date: 2021-08-12
• Subjects: abacavir -- children -- efavirenz -- lopinavir -- malnutrition -- population pharmacokinetics -- rifampicin; Pharmacology -- Periodicals; Drugs -- Periodicals; 615.1
• DOI: 10.1111/bcp.14984
• Languages: English
• ISSNs: 0306-5251

Abstract

Abstract : Aims: Abacavir is part of WHO‐recommended regimens to treat HIV in children under 15 years of age. In a pooled analysis across four studies, we describe abacavir population pharmacokinetics to investigate the influence of age, concomitant medications, malnutrition and formulation. Methods: A total of 230 HIV‐infected African children were included, with median (range) age of 2.1 (0.1–12.8) years and weight of 9.8 (2.5–30.0) kg. The population pharmacokinetics of abacavir was described using nonlinear mixed‐effects modelling. Results: Abacavir pharmacokinetics was best described by a two‐compartment model with first‐order elimination, and absorption described by transit compartments. Clearance was predicted around 54% of its mature value at birth and 90% at 10 months. The estimated typical clearance at steady state was 10.7 L/h in a child weighing 9.8 kg co‐treated with lopinavir/ritonavir, and was 12% higher in children receiving efavirenz. During coadministration of rifampicin‐based antituberculosis treatment and super‐boosted lopinavir in a 1:1 ratio with ritonavir, abacavir exposure decreased by 29.4%. Malnourished children living with HIV had higher abacavir exposure initially, but this effect waned with nutritional rehabilitation. An additional 18.4% reduction in clearance after the first abacavir dose was described, suggesting induction of clearance with time on lopinavir/ritonavir‐based therapy. Finally, absorption of the fixed dose combination tablet was 24% slower than the abacavir liquid formulation. Conclusion: In this pooled analysis we found that children on lopinavir/ritonavir or efavirenz had similar abacavir exposures, while concomitant TB treatment and super‐boosted lopinavir gave significantly reduced abacavir concentrations.