Acute arterial hypoxaemia and its impact on drug pharmacokinetics in humans; clinical and in-vitro investigation.

Abstract

Arterial hypoxaemia ultimately leads to the formation of systemic and localised free radicals, activating pathways of oxidative-inflammatory-nitrosative stress. The physiological adjustments, encompassing redox and haemodynamic responses, have the potential to influence the pharmacokinetics (PK) and pharmacodynamics (PD) of both acutely and chronically administered medications. Sildenafil, a drug that acts through phosphodiesterase-5 inhibition and is clinically used for pulmonary hypertension, also serves as a short-term treatment to prevent or mitigate altitude-induced pulmonary vasoconstriction, a key factor in the development of high-altitude pulmonary oedema (HAPE). This thesis aims to simulate the PK/PD outcomes of sildenafil under acute hypoxaemia and identify the underlying mechanistic pathway that drives PK/PD alterations under hypoxia. The PK/PD profile of a single oral 100 mg sildenafil oral tablet was simulated using R V.3.6.3 with the IQRtools package. A Monte Carlo method was employed, involving 1000 subjects, with a one-compartment first-order elimination and absorption model. The HepaRG cell line served as an in-vitro model to predict the intrinsic clearance (Clint) of sildenafil under hypoxia (1% O2). This was accomplished by evaluating CYP3A4 and CYP2C9 turnover activities and investigating the associated mechanistic pathway. Hypoxia resulted in a significant decrease in the turnover activity of both CYP3A4 and CYP2C9, leading to a 29% reduction in Clint compared to the normoxic control. Monte Carlo simulations revealed that acute hypoxia increased the maximum concentration (Cmax), half-life (t1/2), area under the curve (AUC 0-∞), as well as AUC above the inhibitory concentration 50% (IC50). Hypoxia stimulated stressors such as cytokine and superoxide production, had exerting a negative regulatory effect on CYP3A4/2C9. The preservation of CYP3A4/2C9 activity under hypoxia was achieved by employing reactive oxygen species (ROS) scavengers like Tiron. Furthermore, hypoxia may regulate CYP3A4/2C9 through the modulation of the pregnane x receptor (PXR). The MAPK/ERK signalling pathway appears to be the target pathway for this regulation. In conclusion, hypoxia has the capacity to alter the PK/PD profile of drugs, warranting dosage regimen adjustments, particularly for drugs with narrow therapeutic indices. Further mechanistic studies focusing on the PXR pathway are necessary to fully comprehend the mechanisms underlying hypoxia-induced alterations.