1. Effect of Four Different Meal Types on the Population Pharmacokinetics of Single Dose of Rifapentine in Healthy Male Volunteers Simbarashe P. Zvada 1, Jan-Stefan Van Der Walt 1,2, Peter J. Smith 1, P Bernard Fourie 3, Giorgio Roscigno 4, Dennis Mitchison 5, Ulrika S.H. Simonsson 2, Helen M. McIlleron 1 1 Division of Clinical Pharmacology, Department of Medicine, Stellenbosch University and University of Cape Town, Cape Town, South Africa; 2 Department of Pharmaceutical Biosciences, Uppsala University, Sweden; 3 Medicine in Need South Africa, Pretoria, South Africa; 4 Foundation for Innovative New Diagnostics, Geneva, Switzerland; 5 St. George’s Hospital Medical School, London, United Kingdom

2. Introduction Rifapentine (RFP) is used for TB treatment It has higher in-vitro potency than other rifamycins Long elimination half-life Good candidate for shortening the duration of TB treatment Metabolized mainly to active 25-desacetyl rifapentine (25-DRFP) Pharmacokinetic (PK) studies have demonstrated increased rifapentine plasma concentration and exposure after a “high-fat” meal 24

3. Aim To evaluate the effect of 4 meal types on the population pharmacokinetics of single dose of rifapentine and 25- desacetyl rifapentine

4. Methodology Thirty-five healthy male volunteers were enrolled in an open label, randomised, sequential, single dose, five-way crossover study design Administered single 900 mg RFP dose on each occasion after: ◦ high-fat breakfast ◦ high-fat, bulky breakfast ◦ Low-fat, bulky breakfast ◦ Low-fat high fluid breakfast ◦ under fasting conditions

5. Analysis Blood samples collected up to 72 hrs on each occasion were analyzed using high- performance liquid chromatography Pharmacokinetics data were analyzed by nonlinear mixed effects modeling using NONMEM VI

6. Results

7. RFP and 25-DRFP model Best model for the parent drug was a one compartment with transit absorption, two compartment model for the metabolite Time-varying clearance for both parent and metabolite

8. Simbarashe Zvada (PhD Student, UCT) Parameter estimates for RFP

9. Simbarashe Zvada (PhD Student, UCT) Parameter for 25-DRFP

10. Simbarashe Zvada (PhD Student, UCT) Meal Effects Meal % change in oral bioavailability (% RSE) Meal A +85.720.1 Meal B +32.740.4 Meal C +45.729.3 Meal D +48.930.7 Meal A (high-fat breakfast); Meal B (high-fat & bulky breakfast ); meal C (Low-fat & bulky breakfast); Meal D (Low-fat high fluid breakfast)

11. Report, Basic GOF

12. Model validation Parent drug, RFP Major metabolite, 25-DRFP

13. Conclusions One-compartment model with time-varying CL of RFP, and two compartment model with time-varying CL of 25-DRFP best described the PK data. Meal ingestion increased the extent of RFP and 25-DRFP absorption, with greatest effect coming from English breakfast followed by chicken soup Concomitant food intake should be considered when evaluating optimal rifapentine doses in rifapentine-based regimens

14. Recommendations

15. Acknowledgements A/Prof. H McIlleron A/Prof. USH Simonsson Dr. P Denti Dr. JS Van Der Walt Prof. PJ Smith Prof. G. Maartens Pharmacometric group Uppsala Hoeschst Marion Roussel Wellcome Trust

16. Thank you