RESUMO
The development of novel candidate molecules for tuberculosis remains challenging, as drug distribution into the target tissue is not fully characterised in preclinical models of infection. Often antitubercular human dose selection is derived from pharmacokinetic data in plasma. Here, we explore whether whole-body physiologically-based pharmacokinetic (PBPK) modelling enables the prediction of lung exposure to anti-tubercular drugs in humans. Whole-body PBPK models were developed for rifampicin, isoniazid, pyrazinamide, and ethambutol using plasma data in mice as basis for the prediction of lung exposure. Model parameters were subsequently used to extrapolate disposition properties from mouse and determine lung:plasma ratio in humans. Model predictions were compared to biopsy data from patients. Predictions were deemed adequate if they fell within two-fold range of the observations. The concentration vs time profiles in lung were adequately predicted in mice. Isoniazid and pyrazinamide lung exposures were predicted to be comparable to plasma levels, whereas ethambutol lung exposure was predicted to be higher than in plasma. Lung:plasma ratio in humans could be reasonably predicted from preclinical data, but was highly dependent on the distribution model. This analysis showed that plasma pharmacokinetics may be used in conjunction with PBPK modelling to derive lung tissue exposure in mice and humans during early lead optimisation phase. However, the impact of uncertainty in predicted tissue exposure due to distribution should be always investigated through a sensitivity analysis when only plasma data is available. Despite these limitations, insight into lung tissue distribution represents a critical step for the dose rationale in tuberculosis patients.
Assuntos
Etambutol , Tuberculose , Animais , Antituberculosos/farmacocinética , Etambutol/farmacocinética , Humanos , Isoniazida , Pulmão , Camundongos , Pirazinamida , Tuberculose/tratamento farmacológicoRESUMO
INTRODUCTION: Thanks to recent advances in biotechnology, the use of peptides and proteins as drugs has become a concrete clinical reality, and consequently an interesting challenge has emerged for non-parenteral drug delivery. Leuprolide is a synthetic nonapeptide agonist to the luteinizing hormone-releasing hormone (LH-RH) receptor with principal clinical applications for prostate cancer. Although a large number of formulations available, they mainly consist in depot subcutaneous injections or implantable devices. Both of these routes of administration present multiple limitations considering the large clinical applications of this active substance. AREA COVERED: The objective of this review is to critically discuss the formulations currently available on the market for leuprolide optimization and to consider how drug delivery plays an important role in improving the bioavailability of this compound. EXPERT OPINION: Due to its physicochemical properties and its economical market, leuprolide is an interesting candidate for drug delivery to improve the efficacy of existing treatments, dose adjustments, and patient compliance and safety.