Rob van Wijk [1], Oscar Della Pasqua [1,2]
[1] Leiden Academic Centre for Drug Research, Leiden University, and [2] GlaxoSmithKline Research and Development, Clinical Pharmacology Modelling and Simulation
Objectives: Current regimens for tuberculosis (TB) treatment have been defined empirically, making it difficult to evaluate new treatment combinations. To improve dosing decision in early drug discovery and development, an approach is proposed to determine the best dose of current standard of care (SoC) of TB to be used in preclinical species. Given the role of drug concentration, systemic exposure, or duration of exposure above effective levels, treatment conditions in humans will be explored and associated parameters of interest will be calculated to evaluate most suitable dosing regimens in mice.
Methods: Our analysis is based on a series of simulation analysis mimicking clinical and preclinical experimental conditions. Literature pharmacokinetic (PK) models of pyrazinamide, ethambutol, rifampicin and isoniazid [1–4] were implemented using non-linear mixed effect modelling (NONMEM). Pharmacokinetic/pharmacodynamic (PK/PD) indices AUC/MIC, t>MIC and Cmax/MIC [5] were calculated for steady state concentration profiles, based on different dosing regimens. Variability in human pharmacokinetics was accounted for by inclusion of interindividual variability to the model parameters. Allometric scaling from the human profiles to mice was performed to assist in dosing selection in new preclinical studies. The resulting PK profiles were compared with observed data in mice, and differences in the resulting PK/PD indices were assessed.
Results: Simulated human PK profiles at the currently used dosing of SoC show surprisingly limited concentrations above MIC. The different scenarios show variation in indices values within the same population due to weight dependent dosing regimens and across subpopulations due to different absorption and elimination rates. Allometrically scaled models from humans back to mice show different exposure profiles than the observed data. Consequently, PK/PD indices values based on allometry derived PK differ from reality, especially in rifampin.
Conclusions: An approach is developed improving dosing selection in mice, in which allometric modelling is evaluated. This shows that the currently used dosing regimens in preclinical experiments are not representative of the driving PKPD indices of all of the SoC. Moreover, dose selection based on PK/PD index derived from inaccurate interspecies scaling will be unsuitable.
References:
[1] Wilkins JJ, Langdon G, McIlleron H, Pillai G, Smith PJ, Simonsson USH. Variability in the population pharmacokinetics of isoniazid in South African tuberculosis patients. Br J Clin Pharmacol 2011;72:51–62.
[2] Jönsson S, Davidse A, Wilkins J, Van der Walt J-S, Simonsson USH, Karlsson MO, et al. Population pharmacokinetics of ethambutol in South African tuberculosis patients. Antimicrob Agents Chemother 2011;55:4230–7.
[3] Wilkins JJ, Langdon G, McIlleron H, Pillai GC, Smith PJ, Simonsson USH. Variability in the population pharmacokinetics of pyrazinamide in South African tuberculosis patients. Eur J Clin Pharmacol 2006;62:727–35.
[4] Wilkins JJ, Savic RM, Karlsson MO, Langdon G, McIlleron H, Pillai G, et al. Population pharmacokinetics of rifampin in pulmonary tuberculosis patients, including a semimechanistic model to describe variable absorption. Antimicrob Agents Chemother 2008;52:2138–48.
[5] Mouton JW, Ambrose PG, Canton R, Drusano GL, Harbarth S, MacGowan A, et al. Conserving antibiotics for the future: new ways to use old and new drugs from a pharmacokinetic and pharmacodynamic perspective. Drug Resist Updat 2011;14:107–17.
Reference: PAGE 23 () Abstr 3219 [www.page-meeting.org/?abstract=3219]
Poster: Drug/Disease modeling - Infection