Population pharmacokinetics of rifabutin among co-infected children on lopinavir/ritonavir-based antiretroviral therapy
Manna Semere Gebreyesus (1), Roeland Wasmann (1), Helen McIlleron (1), Lubbe Wiesner (1), Paolo Denti (1), Holly E. Rawizza (2,3)
(1) Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Cape Town, South Africa; (2) Brigham and Women’s Hospital, Boston, MA, USA, (3) Harvard T.H. Chan School of Public Health, Boston, MA, USA
Objectives:
Treatment of tuberculosis in children with HIV is challenging due to drug-drug interactions (DDI). Rifampicin, an important component of the standard TB regimen, is a potent inducer of CYP3A4. During co-treatment with lopinavir/ritonavir (LPV/r)-based antiretroviral therapy (ART), it reduces lopinavir concentrations, which means super-boosting with additional ritonavir is necessary (LPV/r ratio of 4:4 is used instead of the standard ratio of 4:1). However, ritonavir has poor tolerability and in resource-limited settings it is rarely available as a single product needed for super-boosting [1]. In adults, it is recommended to substitute rifampicin with rifabutin [2], which is a weak inducer of CYP3A4 and can be used with standard LPV/r. On the other hand, rifabutin is metabolised by CYP3A4, which ritonavir strongly inhibits, thus increasing rifabutin exposure. In adults, rifabutin dose is reduced from 300 mg when used alone to 150 mg during LPV/r co-treatment [3]. In children, a rifabutin dose of 10-20 mg/kg/day is given when used alone, but the optimal dose during LPV/r co-treatment is still unknown, and its pharmacokinetics during HIV/TB co-treatment has not been adequately studied in children [4]. Rifabutin is primarily (> 90%) eliminated by metabolism, of which the main pathways are by arylacetamide deacetylase (AADAC) to 25-desacetyl-rifabutin [5], and by CYP3A4 to hydroxy and desmethyl metabolites [6]. 25-desacetyl rifabutin, the main metabolite, is further cleared by CYP3A4. Both AADAC and CYP3A4 are highly expressed in the small intestine, as well as the liver [6]. High rifabutin and 25-desacetyl-rifabutin concentrations are implicated in adverse effects, mainly reduced neutrophil count [7].
The objective of this analysis was to characterize the pharmacokinetics of rifabutin during co-treatment with LPV/r in paediatric patients by developing a joint parent-metabolite population pharmacokinetic model of rifabutin and 25-desacetyl-rifabutin.
Methods:
Pharmacokinetic data were obtained from prospective studies in Nigerian children with HIV/TB co-infection in three age cohorts, <1 year old, 1-3 years old, and 3-15 years old. The <1 year and 1-3 years old cohorts were ART-naïve prior to the study and received rifabutin-containing TB treatment (15-20 mg/kg/day) for two weeks, after which they started standard LPV/r-based ART and the rifabutin dose was reduced to 2.5-5 mg/kg/day. The 3–15-year cohort were ART-experienced and were switched to LPV/r-based-ART after failing first line ART, and simultaneously started rifabutin-containing TB treatment (2.5 mg/kg/day). Rifabutin and 25-desacetyl-rifabutin concentrations were measured at 0, 2, 4, 8, 12, and 24-hours post-dose at weeks 2, 4, and 6 for the <1 year old, at weeks 2 and 4 for the 1-3 years old, and at weeks 2, 4, and 8 for the 3-15 years old cohorts. Data were analysed using nonlinear mixed effect modelling in NONMEM (v7.5.1). Several structural models were tested for both rifabutin and 25-desacetyl-rifabutin. The metabolite compartment volumes were fixed to the parent volumes, and the fraction of rifabutin metabolised to 25-desacetyl-rifabutin was estimated. Allometric scaling with body weight was used to adjust disposition parameters.
Results:
Included in this analysis were 828 concentrations from 28 patients with a median (range) age and weight of 125 (8-186) months old and 19 (4.5-45) kg, respectively. Rifabutin and 25-desacetyl-rifabutin pharmacokinetics were best described by two two-compartment disposition models with first-order elimination.
For a typical child of 24 kg during co-treatment with LPV/r, apparent rifabutin clearance was estimated as 15.8 L/h, with 90.8% of the rifabutin metabolized to 25-desacetyl-rifabutin, and 25-desacetyl-rifabutin clearance was 26.0 L/h. Without LPV/r co-treatment, bioavailability is 85.4% lower while 25-desacetyl-rifabutin clearance was 4.3-fold higher.
Conclusions:
Concomitant administration of rifabutin and LPV/r increases systemic rifabutin and 25-desacetyl-rifabutin exposure, through increasing bioavailability and decreasing 25-desacetyl-rifabutin clearance, likely due to CYP3A4 inhibition. While rifabutin levels are adjusted for the interaction, the 25-desacetyl-rifabutin is higher with LPV/r, thus potentially increasing the risk of lowered neutrophil count. There is therefore a need to optimize rifabutin dose and to investigate safety of higher 25-desacetyl-rifabutin concentrations when cotreating.
References:
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