Pharmacokinetics of abacavir and lamivudine in infants with and without rifampicin co‐treatment

12 Introduction: Fixed-dose combination (FDC) paediatric formulation of lamivudine/dolutegravir/abacavir was recently licensed by the FDA for the treatment of HIV in children and is expected to be used frequently in low- and middle-income countries. In children living with HIV diagnosed with drug-sensitive tuberculosis, rifampicin is added, which induces UDP-glucuronosyltransferases and renal transporters. These proteins are also involved in the metabolism of lamivudine and abacavir. However, limited pharmacokinetic data are available to quantify this effect. Objective: This study evaluated the impact of rifampicin on the pharmacokinetics of abacavir and lamivudine in infants aged between 28 and 365 days and weighing more than 3 kg. Methods: This was a pharmacokinetic study nested within the EMPIRICAL trial, a multicentre study. Eighteen infants living with HIV were recruited at clinical sites in Mozambique, Uganda, Zambia and Zimbabwe. They were receiving a once-daily fixed-dose combinations (FDC) of abacavir/lamivudine, 20 mg/60 mg if weighing between 3 and <6 kg and 120 mg/60 mg if weighing between 6 and <10 kg, in combination with dolutegravir dispersible tablets, following WHO dosing guidelines. The participants were divided into two groups: a control group (n = 5) receiving only ART and an experimental group (n = 13) receiving ART with added rifampicin for tuberculosis treatment. Residual blood samples from a previous pharmacokinetic sub-study collected at pre-dose and at 2, 4, 6 and 8, and 12/24 h post-dose were used. Pharmacokinetic parameters (AUC₀–₂₄h, t₁/₂, Vd/F, and CL/F) were analysed using WinNonlin version 8.3. Results were reported as geometric means and coefficients of variation (%CV). The study adhered to ethical and legal standards as outlined in the main EMPIRICAL study protocol. Results: A total of 18 infants were enrolled. The overall median age was 6.6 months (range: 3.2–11.9), and the median weight was 6.0 kg (range: 3.8–8.2). In the control arm, the median age was 7.1 months (range: 6.2–11.1), whereas in the rifampin arm, it was 6.3 months (range: 3.2–11.9). The median weight in the control arm was 6.0 kg (range: 5.7–8.2), while in the rifampicin arm, it was 5.9 kg (range: 3.8–8.0). Regarding pharmacokinetic parameters, abacavir GM(%CV) AUC0-24h was 21.0 (19) h × mg/L in infants without rifampicin and 21.9 (74) h × mg/L in infants co-treated with rifampicin. Abacavir GM(%CV) Cmax was comparable for children without and with rifampicin (6.3 (55) vs. 6.2 (10) mg/L, respectively) as well as the apparent clearance (6.7 vs. 6.0 mL/min, resp.) half-life (2.47 vs. 1.91 h, resp.). For lamivudine, the GM(%CV) AUC0-24h was comparable in both study arms with 12.4 (37) h × mg/L for children without rifampicin and 12.6 (49) h × mg/L for those using rifampicin as well as the apparent clearance (5.7 vs. 5.2 mL/min, respectively). Lamivudine GM was 22% higher in children taking rifampicin (2.4 (52) vs. 1.9 (21) mg/L) and GM half-life was 48% shorter (2.50 vs. 4.79 h). Conclusion: Rifampicin co-treatment had minimal impact on the pharmacokinetics of lamivudine and abacavir. These findings suggest that dosage adjustments are not necessary for lamivudine/abacavir during concomitant rifampicin-containing TB treatment in children.