Pharmacokinetic data of lopinavir/ritonavir in second-line treatment of African children living with HIV

Abstract

15

Pharmacokinetic data of lopinavir/ritonavir in second-line treatment of African children living with HIV

Anne Kamphuis¹, Hylke Waalewijn^1,2, Alexander Szucbert³, Chishala Chabala⁴, Mutsa Bwakura-Dangarembizi⁵, Shafic Makumbi⁶, Joan Nangiya⁶, Vivian Mumbiro⁵, Veronica Mulenga⁴, Victor Mussiime⁶, David Burger¹, Diana Gibb³ and Angela Colbers¹

¹Radboud Research Institute for Medical Innovation (RIMI), Radboudumc; ²Division of Clinical Pharmacology, Department of Medicine, University of Cape Town; ³Medical Research Council Clinical Trials Unit at University College London; ⁴University Teaching Hospital; ⁵University of Zimbabwe Clinical Research Centre; ⁶Joint Clinical Research Centre

Background: Children living with HIV require specific strengths and formulations of antiretrovirals. Lopinavir/ritonavir (LPV/r) is recommended by the WHO for children as preferred bPI for second-line. As paediatric 100/25 mg tablets have inconsistent availability in some countries, using adult 200/50 mg tablets for children could simplify procurement. For children weighing 25–34.9 kg, the daily recommended dose of 600/150 mg could be achieved by dosing two 200/50 mg tablets in the morning and one in the evening, instead of three 100/25 mg tablets twice daily (current WHO-recommendation). In CHAPAS-4 (#ISRCTN22964075), second-line treatment options for children with HIV were investigated. We performed a nested PK substudy to evaluate LPV/r exposure in children with different NRTI backbones.

Methods: Children with HIV aged 3–15 years failing NNRTI-based first-line treatment were randomized to four anchor drugs with emtricitabine/tenofovir alafenamide or standard-of-care NRTIs (abacavir or zidovudine with lamivudine). Children weighing 14–24.9 kg received 200/50 mg LPV/r twice daily; children weighing 25–34.9 kg received 400/100 mg LPV/r in the morning and 200/50 mg in the evening; and children weighing ≥35 kg received 400/100 mg LPV/r twice daily. At steady state, PK blood samples were taken at pre-dose, 1, 2, 4, 6, 8 and 12 h after LPV/r intake with food. LPV concentrations were measured using a validated HPLC method. Lopinavir AUC_0–12 h, C_max and C_trough were calculated using non-compartmental analysis. PK data of children receiving similar dosages were used for comparison. The individual target C_trough was defined as 1.0 mg/L. Statistical analysis was performed using ANOVA on log-transformed values with Tukey post hoc analysis to detect differences in LPV PK parameters between weight bands and NRTI backbones.

Results: Fifty-one children were included in this substudy. Eleven children were excluded for varied reasons. There were nine children in the 14–19.9 kg weight band, 10 in 20–24.9 kg, 9 in 25–34.9 kg and 12 in ≥35 kg. The overall geometric mean (GM), (CV%) AUC_0-12 h was 116.15 h*mg/L (37%) and the GM (CV%) C_max was 12.52 mg/L (32%), which is comparable to the reference AUC_0–12 h and C_max. The GM (CV%) C_trough of 7.71 mg/L (52%) in this sub-study is ∼57% higher than the reference value, and near to the C_trough associated with dyslipidaemia in adults (8 mg/L), possibly explaining why CHAPAS-4 children on LPV/r showed the least favourable lipid profiles. The C_trough and the C_max were significantly higher in children weighing 25–34.9 kg (11.7 and 15.38 mg/L) compared to children in the 14–19.9 kg and ≥35 kg weight-bands (6.19 and 12.52 mg/L; 6.96 and 12.10 mg/L, respectively); p-values ranging from 0.021 to 0.048. These children received a higher milligram per kilogram body weight dose in the morning compared to children in the other weight bands. There was no difference in PK parameters when comparing according to backbone.

Conclusions: This PK sub-study shows that the AUC_0–12 h and C_max of LPV after administration of LPV/r with food in children 3–15 years of age weighing ≥14 kg on second-line treatment is comparable to reference data of children. In addition, it shows that the use of the adult LPV/r 200/50 mg tablet could potentially be extended from the currently WHO-recommended 35 kg down to 25 kg. Relatively high C_trough concentrations may be associated with dyslipidaemia.