A population pharmacokinetic model for rifampicin auto induction

Transcription

1 A population pharmacokinetic model for rifampicin auto induction Paolo Denti 1, Wynand Smythe 1, Ulrika SH Simonsson 2, Roxana Rustomjee 3, Philip Onyebujoh 4, Peter Smith 1, Helen McIlleron 1 1 Division of Clinical Pharmacology, University of Cape Town, South Africa; 2 Department of Pharmaceutical Biosciences, Uppsala University, Sweden; 3 TB Research Unit, South African Medical Research Council, Durban, South Africa 4 Special Programme for Research and Training in Tropical Diseases, WHO, Geneva, Switzerland

2 Introduction In 2008, there were an estimated 9.4 million incident cases worldwide, and more than 40k in South Africa (WHO 2009)

3 Rifampicin Rifampicin is the backbone of 1 st line TB treatment, and its efficacy is concentrationdependent Rifampicin believed to be metabolized by a beta esterase. It is a potent inducer of PXR mediated pathways and thus reduces the concentrations of numerous concomitantly administered drugs, including itself. Rifampicin auto induction is believed to take about a week (Niemi et al. 2003), but neither the onset nor the magnitude of the phenomenon have been adequately described. M. Niemi, J.T. Backman, M.F. Fromm, P.J. Neuvonen, and K.T. Kivistö, "Pharmacokinetic interactions with rifampicin : clinical relevance.," Clinical pharmacokinetics, vol. 42, 2003, pp

4 Aim To describe auto induction quantitatively in South African patients: Progression (how long?) Extent (how much?) Pregnane X Receptor

5 Material and Methods 61 South African, HIV+, TB patients (33 females and 28 males) Rifampicin, isoniazid, pyrazinamide, ethambutol were given as FDC once daily in the morning. Most patients received TB treatment days per week, were on 7 days per week regimen. Doses were adjusted according to body weight, following WHO guidelines Samples were taken on day 0, 7, 14 and 28 at time 0, 1, 2, 4, 6, 8, 12 hours after dose Covariate Median Range Weight [kg] Height [m] Fat Free Mass [kg] Age [years] CL/F and V/F were allometrically scaled The method FOCE I with NONMEM VII was employed Changes in the PK parameters due to auto induction were investigated.

6 Structural Model Dose Biovailability (F) 1.04 h 1 BOV 67% 4.6 L/42.2kg BSV 13.8% BOV 1.7% Absorption Cmpt Ka Central Cmpt Series of transit compartments 34.6 Meat Transit Time (MTT) + Number of Trans Cmpts (NN) h BOV 74.4% CL/V Before accounting for auto induction: 11 L/h/42.2kg BSV 18.% BOV 42.3% J.J. Wilkins, R.M. Savic, M.O. Karlsson, G. Langdon, H. McIlleron, G. Pillai, P.J. Smith, and U.S. Simonsson, "Population pharmacokinetics of rifampin in pulmonary tuberculosis patients, including a semimechanistic model to describe variable absorption.," Antimicrobial agents and chemotherapy, vol. 2, 2008, pp

7 Auto induction CL [L/h] Clearance vs Days on Treatment CL CL bas CL SS CL bas e ln 2 t 1 2 t Days after beginning of TB treatment

8 Visual Predictive Check 1 DAY 0 DAY 7 1 Observations (Pred and Var Corr) Time after dose (hours) Time after dose (hours) 1 DAY 14 DAY 28 1 Observations (Pred and Var Corr) Time after dose (hours) Time after dose (hours)

9 Parameter values Parameter Typical Value (%RSE) BSV (%RSE) BOV (%RSE) CL Baseline [L/h/42.2kg*] 6.94 (.7%) 2.2% (19.%) 23.2% (7.%) CL Steady State [L/h/42.2kg*] 1.1 (7%) 2.2% (19.%) 23.2% (7.%) t ½ [days] 6.04 (23.%) VOL [L/42.2kg*] 4.6 (2.7%) 13.8% (19.8%) 1.7% (.7%) K a [h 1 ] 1.07 (7.4%) 67% (.9%) MTT (Mean transit time) [h] (6.7%) 74.4% (8.3%) NN (Number of trans cmpts) 34.6 (1.2%) PROP ERR (%) 11.6% (2.9%) ADD ERR [mg/l] (.%) ADD ERR BLQ [mg/l] 0.04 (FIXED) *CL and V are reported for a 42.2 fat free mass subject, and scaled according to Anderson and Holford, 2008 B.J. Anderson and N.H. Holford, "Mechanism based concepts of size and maturity in pharmacokinetics.," Annual review of pharmacology and toxicology, vol. 48, 2008, pp

10 Conclusions We quantified rifampicin auto induction: progression and extent Clearance doubles (2.18 fold) from first dose to steady state (6.94 to 1.1) 0% effect is reached in 6 days, full induction (~97%) about a month Accounting for auto induction is useful in the design of drug interaction studies and PK/PD modeling of early therapeutic effect Further study is necessary to investigate auto induction beyond 1 month of treatment

11 Acknowledgments The UCT Pharmacology lab for performing the assay WHO and TDR, which sponsored the TB HAART study The PKPDia consortium, funded by the Wellcome Trust programme grant 374 All my colleagues in the pharmacometrics lab at the UCT Division of Clinical Pharmacology Virology Education for sponsoring my attendance of this workshop