II-58 Lufina Tsirizani

A pooled pharmacokinetic analysis of rifampicin, isoniazid, and pyrazinamide in paediatric patients with tuberculosis.

Lufina Tsirizani Galileya(1), Roeland E. Wasmann(1), Chishala Chabala(1,2,3), Helena Rabie(4), Janice Lee(5), Irene Njahira Mukui (5), Mark F. Cotton (4), Anna Turkova(6), Diana Gibb(6), Helen M. McIlleron(1,7), Paolo Denti(1)

(1) Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Cape Town, South Africa. (2) University of Zambia, School of Medicine, Department of Paediatrics, Lusaka, Zambia. (3) University Teaching Hospitals-children’s Hospital, Lusaka, Zambia. (4) Department of Pediatrics and Child Health and Family Center for Research with Ubuntu, University of Stellenbosch, Cape Town, South Africa. (5) Drugs for Neglected Diseases Initiative, Geneva, Switzerland (6) Medical Research Council–Clinical Trials Unit at University College London, Institute of Clinical Trials and Methodology, London, United Kingdom. (7) Wellcome Centre for Infectious Diseases Research in Africa (CIDRI-Africa), Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Cape Town, South Africa.

INTRODUCTION: HIV and tuberculosis (TB) co-infection is common in resource limited settings (1). There have been inconsistent findings on the effect of HIV-infection on the pharmacokinetics (PK) of TB drugs in adults (2,3), possibly owing to the confounding effect different antiretroviral therapies (ART). There is a paucity of data on the effect of HIV and ART on the PK of TB drugs in children. We report a pooled PK analysis of multiple studies of children on first-line anti-TB drugs. The studies recruited HIV+ and HIV- children and we evaluated effects of age, weight, body size, HIV, ART, and other factors on the PK of first-line TB drugs in children.

METHODS: Using non-linear mixed-effects modelling, we characterized the population PK of rifampicin (RIF), isoniazid (INH), and pyrazinamide (PZA) with data pooled from three studies: SHINE, a randomized trial  of a shortened (4 versus 6 months) first-line regimen using WHO-recommended doses in children with non-severe TB; DNDi, a phase I/II  open-label, sequential non-randomized study comparing the PK of lopinavir when super-boosted (4:4 ratio) during TB treatment with standard lopinavir/ritonavir (LPV/r, 4:1 ratio) doses after treatment; and DATiC, a PK study of optimal dosing of first-line TB drugs and ART in children.  All children in the three studies underwent intensive PK blood sampling and samples were assayed with LC-MS/MS.

 For each drug, we tested one- and two-compartment models with first-order absorption with either transit compartments or lag time. We explored first-order and saturable elimination. 142 children in the DATiC study had N-acetyltransferase 2 (NAT2) genotype information. We used a mixture model to assign children with unknown NAT2 genotype to either slow, intermediate, or fast acetylator status.  We tested the effect of body size, age, weight, ART, HIV and drug formulation.

 RESULTS: Data from 394 children from Malawi, Zambia, India and South Africa was available for analysis, with median (range) age and weight of 2.1 (0.22-15) years and 10.8 (3.20-59.3) kg, respectively. 47% were female and 148 (37.3%) were HIV+ with 95% on ART. We quantified 2625, 1996, and 1865 concentrations for RIF, INH and PZA, respectively.

 A one-compartment disposition model with first-order elimination from a liver compartment (with first-pass effect) best described RIF, while a two- and one-compartment model with first-order elimination best described INH and PZA, respectively.

 After including allometry, maturation of clearance, the effect of age on bioavailability for RIF and INH, and NAT2 genotype for INH, we investigated the effect of HIV and ART. We found that children on LPV/r had 21% lower RIF clearance and 49% higher PZA clearance. Additionally, children taking LPV/r at the same time as the TB medications had 39% lower INH bioavailability. Finally, children on efavirenz (EFV) had 38% lower INH bioavailability. We found no change in clearance and/or bioavailability of RIF, INH, or PZA in HIV+ children who were not yet on ART. The R-cin RIF formulation had 70% less RIF bioavailability and the McLeod’s adult formulation had 38% lower INH bioavailability compared to other formulations.

 CONCLUSION: We confirm previous reports that LPV/r reduces clearance of RIF, leading to higher RIF exposure (3). The potential mechanism could be LPV/r’s inhibition of p-glycoprotein and OATP 1 and 3, transporters for which RIF is a substrate (4). We found that LPV/r increased clearance of PZA, which is metabolized by xanthine oxidase (XO). Ritonavir activates NADPH oxidase (5) and is thought to also activate XO, which would increase PZA clearance (6). The observed reduction in INH bioavailability when LPV/r was taken at the same time as TB drugs could be due to the high fructose (15.3% w/v) in the LPV/r Kaletra formulation used in all three studies (7), since condensation of INH when mixed with different sugars has been previously reported and may have led to lower absorption (8,9).  The reduction in INH exposure with EFV has been previously reported (10). We found no change in the PK of RIF, INH and PZA in HIV+ children not yet on ART. Previous reports linking HIV infection to PK changes in TB drugs in children may have been due to ART instead of HIV infection. We recommend further confirmation of the new findings of the effect of LPV/r on the PK of INH and PZA as unaccounted for confounders cannot be excluded.

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Reference: PAGE 30 (2022) Abstr 10190 [www.page-meeting.org/?abstract=10190]

Poster: Drug/Disease Modelling - Paediatrics