Jose Francis (1), Simbarashe P. Zvada (1,2), Paolo Denti (1), Mark Hatherill (3,4), Salome Charalambous (5), Stanley Mungofa (6), Rodney Dawson (7), Susan Dorman (8), Nikhil Gupte (8), Lubbe Wiesner (1), Amina Jindani (9), Thomas Harrison (10), Deirdre Egan (10), Andrew Owen (10), Helen M. McIlleron (1,4).
1) Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, South Africa; 2) Division of Clinical Pharmacology, Stellenbosch University, Cape Town, South Africa; 3) South African Tuberculosis Vaccine Initiative (SATVI) and School of Child and Adolescent Health; 4) Institute of Infectious Disease and Molecular Medicine, University of Cape Town, South Africa; 5) Aurum Institute for Health Research, South Africa;6) Harare City Health Department, Ministry of Health, Zimbabwe;7) Division of Pulmonology, Department of Medicine, University of Cape Town Lung Institute, Cape Town, South Africa;8) Johns Hopkins University School of Medicine, Baltimore, Maryland, USA; 9) Institute for Infection and Immunity, St. George’s, University of London; 10) Department of Pharmacology and Therapeutics, University of Liverpool, Liverpool, United Kingdom.
Objectives: Rifamycins play a key role in the multidrug treatment of tuberculosis. With its long half-life and excellent sterilizing activity, rifapentine is an attractive alternative to rifampicin and is increasingly used to treat active tuberculosis and latent infection. Like rifampicin, rifapentine demonstrates marked interpatient pharmacokinetic variability and its primary metabolic pathway involves deacetylation to 25-desacetyl rifapentine, which is mediated by human arylacetamide deacetylase (AADAC). The absorption of rifapentine is markedly increased by concomitant food administration. Like other rifamycin’s, rifapentine is also known to cause autoinduction of its own metabolism. The success of anti-tuberculosis treatment is related to rifapentine concentrations, therefore single nucleotide polymorphisms substantially influencing its concentrations may be of therapeutic importance. The exposure of rifamycin’s in humans is modulated by pregnane X receptor (PXR), constitutive androstane receptor (CAR) and solute carrier organic anion transporter (SLCO1B1) genes. The aim of this study was to determine the effect of functionally significant polymorphisms of SLCO1B1, PXR, CAR, and AADAC on rifapentine exposure.
Methods: The study included patients diagnosed with pulmonary tuberculosis from two clinical studies (RIFAQUIN and a two-stage activity-safety study of daily rifapentine referred to as “Daily RPE”) [1,2]. In RIFAQUIN, rifapentine was administered in the continuation phase of anti-tuberculosis treatment either as 1200 mg once weekly or 900 mg twice weekly. In Daily RPE 450 or 600 mg were given daily during the intensive phase of treatment. For RIFAQUIN, pharmacokinetic assessment involved a rich (with a pre-dose and samples at 1, 2, 3, 5, 7, 10, 12, 26, and 50 h after dosing) or sparse sampling (samples drawn around 2, 5, and 24 or 48 h after dosing). The pharmacokinetic sampling for Daily RPE was done at approximately one month after starting therapy and samples were obtained either with a rich sampling schedule (with a pre-dose and samples at 0.75, 1.5, 3.5, 5, 12, and 24 h after dose), or sparse sampling (0.5-2 h and 5-8 h after dose). The plasma rifapentine concentrations were determined with a validated LC-MS/MS assay using rifaximin as internal standard. The lower limit of quantification (LLOQ) was 0.156 mg/L. Pharmacogenetic information was obtained by genotyping in a subset of patients from these studies. The pharmacokinetic data was analysed using NONMEM 7.4 with FOCE-I. The influence of gene polymorphism on rifapentine pharmacokinetics for patients with unknown genotype was identified using mixture modelling [3].
Results: A total 1144 drug concentration measurements were available for the final analysis, collected from 326 patients who are southern Africans with a median body weight and age of 56 kg and 32 years respectively. Pharmacogenetic information was available for 162 patients. The few observations below the LLOQ (n=7) were omitted from the analysis. A one compartment model with first order elimination and transit compartment absorption described the data well [4]. Allometric scaling with fat free mass for clearance and total body weight for volume of distribution were found to be best size predictors. In a typical patient, the values of CL and Vd were 1.33 L/h and 25 litres respectively. Patients who were homozygous for AADAC rs1803155 AA mutation were found to have 10.4% lower clearance. Patients who were infected with HIV had 21.9% lower bioavailability. Those dosed with 1200 mg weekly were found to have 13.2% lower clearance compared to the other dose groups. Additionally, the Daily RPE study had 23.3% lower bioavailability when compared to RIFAQUIN study.
Conclusions: Our study is the first to show that the AADAC rs1803155 (AA) polymorphism is associated with low rifapentine clearance, leading to increased rifapentine exposure, although the size of the effect detected is unlikely to be of clinical significance Additionally, we found that rifapentine exposure was lower in HIV infected patients which is consistent with previous findings on rifamycin’s. The patients in 1200 mg dose group were given the drug in less frequent dosing schedule which may have led to less pronounced auto-induction. The study effect detected is likely linked to differences in food pattern across the studies, highlighting the importance of standardising this aspect when studying PK of rifapentine.
References:
[1]Jindani A, Harrison TS, Nunn AJ, Phillips PPJ, Churchyard GJ, Charalambous S, Hatherill M, Geldenhuys H, McIlleron HM, Zvada SP, Mungofa S, Shah NA, Zizhou S, Magweta L, Shepherd J, Nyirenda S, van Dijk JH, Clouting HE, Coleman D, Bateson ALE, McHugh TD, Butcher PD, Mitchison DA. 2014. High-Dose Rifapentine with Moxifloxacin for Pulmonary Tuberculosis. N. Engl. J. Med. 371:1599–1608.
[2] Dawson R, Narunsky K, Carman D, Gupte N, Whitelaw A, Efron A, Barnes GL, Hoffman J, Chaisson RE, McIlleron H, Dorman SE. 2015. Two-stage activity-safety study of daily rifapentine during intensive phase treatment of pulmonary tuberculosis. Int. J. Tuberc. Lung Dis. 19:780–786.
[3]Keizer RJ, Zandvliet AS, Beijnen JH, Schellens JHM, Huitema ADR. 2012. Performance of Methods for Handling Missing Categorical Covariate Data in Population Pharmacokinetic Analyses. AAPS J 14:601–611.
[4]Savic RM, Jonker DM, Kerbusch T, Karlsson MO. 2007. Implementation of a transit compartment model for describing drug absorption in pharmacokinetic studies. J. Pharmacokinet. Pharmacodyn. 34:711–26.
Reference: PAGE 27 (2018) Abstr 8695 [www.page-meeting.org/?abstract=8695]
Poster: Drug/Disease Modelling - Infection