Morris Muliaditan (1,2), Donato Teutonico (3), Fatima Ortega (4), Santiago Ferrer (4), Oscar Della Pasqua (1,2)
(1) UCL School of Life and Medical Sciences, London, UK, (2) GlaxoSmithKline, London, UK, (3) Bayer Technology Services, Leverkusen, Germany, (4) GlaxoSmithKline Diseases of Developing World (DDW) Medicines Development Campus, Tres Cantos, Madrid, Spain.
Objectives: The rationale underpinning dosing regimens of modern short-course therapy for tuberculosis (TB) remains empirical. Characterising the time course of drug concentrations in the lung can provide better understanding of the exposure-response relationship at the site of action and inform a more robust dose rationale. A physiologically-based pharmacokinetic (PBPK) model in mice was developed using isoniazid (INH) and rifampicin (RMP) as paradigm compound. Human lung tissue and plasma concentration were predicted from the mice PBPK model with the objective of highlighting the difference between drug exposure in plasma and in tissue.
Methods: Mouse plasma INH concentrations were collected following a single 10 mg/kg intravenous (IV) or 0.1-25 mg/kg oral (PO) administration. Plasma RMP concentrations were collected following single 12 mg/kg IV or 1-100 mg/kg PO, supplemented with literature data from mice who received single dose 0.33- 810 mg/kg PO (1). Lung tissue concentrations were measured after administration of 0.5, 5 and 25 mg/kg (INH) or 10 and 100 mg/kg (RMP). Predicted human plasma AUC0-24 were compared against simulated values using published PK models (2,3). Plasma and lung concentration versus time profiles based on WHO recommendations were simulated in virtual patients. The adequacy of each regimen was assessed taking into account the variability in AUC0-24. Population PK simulations were performed in NONMEM 7.3 and the PBPK model was developed in PK-Sim and MoBi (4). All animal studies were ethically reviewed and carried out in accordance with European Directive 86/609/EEC and the GSK Policy on the Care, Welfare and Treatment of Animals.
Results: The PBPK model adequately described INH and RMP lung tissue concentration in mice and closely predicted human plasma concentrations. The median INH AUC0-8 plasma to lung ratio was 1.03, 1.05 and 0.91 after administration of respectively 0.55, 5.11 and 25.70 mg/kg, whereas the RMP median AUC0-8 plasma-lung ratio was 0.48 and 1.25 following 10 and 100 mg/kg. Evaluation of the weight bands revealed that WHO recommended regimens yielded the lowest exposure in patients weighing less than 40 kg.
Conclusion: In summary, current analysis suggests that INH levels in tissue do not differ considerably from levels in plasma whereas RMP exposure in the lung is dose dependent. Patients with less than 40 kg are potentially underexposed to both drugs as compared to those with higher body weight.
References:
[1] Jayaram R et al. (2003). Pharmacokinetics-Pharmacodynamics of Rifampin in an Aerosol Infection Model of Tuberculosis. Antimicrob Agents Chemother 47: 2118-24
[2] Wilkins J et al. (2011). Variability in the population pharmacokinetics of isoniazid in South African tuberculosis patients. Br. J Clin Pharmacol 71:51-62
[3] Smythe et al. (2012). A Semimechanistic Pharmacokinetic-Enzyme Turnover Model for Rifampin Autoinduction in Adult Tuberculosis Patients. Antimicrob. Agents Chemother 56: 2091-2098
[4] Eissing T et al. (2011). A computational systems biology software platform for multiscale modeling and simulation: integrating whole-body physiology, disease biology, and molecular reaction networks. Front. Physio 24: 2-4
Reference: PAGE 25 (2016) Abstr 6041 [www.page-meeting.org/?abstract=6041]
Poster: Drug/Disease modeling - Absorption & PBPK