III-55 Louvina van der Laan

Pharmacokinetics and drug-drug interactions of lamivudine and abacavir administered with antituberculosis drugs in HIV-infected children with multidrug-resistant tuberculosis

Louvina E. van der Laan1,2, Anthony J. Garcia-Prats2, H. Simon Schaaf2, Jana Winckler2, Heather Draper2, Lubbe Wiesner1, Jennifer Norman1, Helen McIlleron1, Anneke C. Hesseling2 , Paolo Denti1

1 Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, South Africa.2 Desmond Tutu TB Centre, Department of Paediatrics and Child Health, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa

Objective

An estimated 2.1 million children (<15 years) were living with HIV in 2016(1), the majority in sub-Saharan Africa, where tuberculosis (TB) and HIV epidemics coincide. WHO recommends lamivudine (3TC) and abacavir (ABC) as preferred dual nucleoside reverse transcriptase (NRTI) backbone for first-line antiretroviral treatment (ART) in HIV-infected children (>3 months)(2). As multidrug-resistant (MDR)-TB frequently occurs in young children in settings with high burden of TB and HIV(3), it is important to identify potential interactions between MDR-TB treatment and NRTIs. 3TC is primarily renally eliminated(4), it has low protein binding (generally <36%)(5, 6) and induces p-glycoprotein(7). ABC is extensively metabolised by the liver(8, 9), primarily via urine diphosphate glucuronyltransferase and alcohol dehydrogenase(10), protein binding is 50% and it is a substrate and possible inhibitor of p-glycoprotein(11–13). These are all sites for possible drug-drug interactions (DDIs) with MDR-TB drugs. We describe the pharmacokinetics (PK) of and potential DDIs, between 3TC, ABC and drugs routinely used for MDR-TB treatment in HIV-infected South African children.

Methods

54 HIV-infected children established on a NRTI-containing ART regimen (only 50 on ABC) were included, in two groups: MDR-TB treatment group (n=27) receiving individualised MDR-TB treatment based on the drug susceptibility of the child or known source case (including combinations of high-dose isoniazid, pyrazinamide, ethambutol, ethionamide, terizidone, a fluoroquinolone, and amikacin) and an HIV-infected non TB control group (n=27). 3TC and ABC were dosed as per South African guidelines(14). All children were on combination ART containing either lopinavir/ritonavir or efavirenz. Participants were sampled at 6 time points: 1 hour and immediately before ART dosing, and at 1, 3, 7, and either 5 or 10 hours post ART dosing. Samples were processed with liquid-liquid extraction method using ethyl acetate, followed by LC-MS/MS detection. LLOQ for both drugs were 0.024 mg/L. NONMEM 7.4.3 with FOCE-I was used to develop the population PK model. PsN, Pirana and Xpose were used in the model building process for data exploration, visualization and creation of diagnostics(15). Allometric scaling(16) was used to account for the effect of body size, using either total body weight or fat-free mass(17). Age was tested using a sigmoid Emax maturation model(16, 18). BLQ values were handled by the M6 method(19) and for all imputed values, the additive error was inflated by LLOQ/2.

Results

The median (interquartile range) age and weight were 4.2 (1.6-9.6) years and 13.4 (9.1-21.4) kg for the MDR-TB group and 5.7 (1.6-9.5) years and 15.6 (11.2-23.1) kg for the control group. 3TC [ABC] was given as a suspension (52%) [64%] or tablet (48%) [36%]. Two-compartment models with first-order elimination and transit compartment absorption described the PK of 3TC and ABC. Allometric scaling with body weight adjusted for the effect of body size, after which maturation could be identified: clearance was predicted to reach half its mature value 2 months after birth for 3TC and 3 months after birth for ABC, with both drugs being fully mature 2 years of age. Since the maturation parameters could not be identified precisely, Bayesian priors(20) based on reports from larger comparable populations(21)(22); 20% uncertainty was used to stabilize the models. The typical clearance in a 15-kg child was estimated at 10.8 L/h for 3TC and 16.3 L/h for ABC. The mean absorption transit time (MTT) for the suspension formulation was significantly faster than tablets (21 vs 39 min 3TC; 5 vs 27 min ABC), with no effect found on bioavailability. No significant difference in bioavailability, clearance, or absorption could be detected between the MDR-TB treatment and control group, as well as the lopinavir/ritonavir and efavirenz containing combination ART.

Conclusions

No significant effect was found on key PK parameters of 3TC and ABC when co-administered with routine drugs used for MDR-TB in HIV-infected children. Both 3TC and ABC suspensions had significantly faster MTT compared to tablets. While these findings need to be considered in the context of the modest sample size, they are reassuring and suggest the absence of major DDIs between 3TC, ABC and the MDR-TB drugs in our study. DDIs require further studies in newer MDR-TB drugs including bedaquiline, delamanid and linezolid, in HIV-infected children.

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Reference: PAGE 28 (2019) Abstr 9037 [www.page-meeting.org/?abstract=9037]

Poster: Drug/Disease Modelling - Paediatrics

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