Decreased Cytochrome P450 3A activity in palliative patients with haematological diseases: Potential impact on supportive drug therapies

Abstract

Cytochrome P450 3A (CYP3A) is the most relevant drug‐metabolizing enzyme in human beings involved in the elimination of about 50% of the marketed drugs. Comprehensive in vivo data of CYP3A activity in palliative patients with haematological diseases are missing. Therefore, CYP3A activity was determined under real‐life clinical conditions in patients to gain knowledge about dose adjustments for supportive therapies and symptom management in haematology. The single‐arm, prospective trial obtained a 4‐hours pharmacokinetic profile of midazolam after oral administration of a microdose as marker substance from each enrolled patient. Plasma concentrations of midazolam and its primary metabolite 1′‐hydroxy‐midazolam were quantified by mass spectrometry techniques. CYP3A activity was calculated as partial metabolic clearance from an established limited sampling area under the curve. All other drugs taken by the participating patients were considered as well as recent laboratory test results and the patients' diagnoses. Partial metabolic clearance of midazolam in patients with haematological diseases was highly variable (36.9 ± 52.7 L/h). In comparison with the CYP3A activity of healthy individuals, this was a highly significant 30% reduction of activity (P < 0.0001). Dosing of major CYP3A substrate drugs needs to be reduced in palliative patients with haematological diseases, otherwise escalation of debilitating symptoms due to drug interactions might occur.

Absolute Bioavailability of Microdosed Midazolam After Buccal Administration Is Dependent on Buccal Exposure Time

“…In recent years, microdosed midazolam has become increasingly popular because of the absence of pharmacological effects with this low dose. 8,[17][18][19] A major obstacle is that no microdosed oral formulation is commercially available and therefore intravenous solutions are diluted to obtain the required dose, which is then orally administered as a drinking solution. Therefore, this technique is restricted to dedicated trial centers and is not a widely used methodology.…”

“…Because regulatory agencies require drug‐drug interaction studies covering the major drug‐metabolizing enzymes, midazolam is often used during clinical drug development. In recent years, microdosed midazolam has become increasingly popular because of the absence of pharmacological effects with this low dose 8,17–19 . A major obstacle is that no microdosed oral formulation is commercially available and therefore intravenous solutions are diluted to obtain the required dose, which is then orally administered as a drinking solution.…”

CYP3A Activity in End-of-Life Cancer Patients Measured by 4β-Hydroxycholesterol/cholesterol Ratio, in Men and Women

“…In fact, there are few studies on CYP3A activity in the basal state in cancer patients, as most studies have been performed investigating cytotoxic agents where potential inducing or inhibiting effects on CYP3A has been the primary aim of the study [ 12 , 13 ]. Additionally, previous studies on CYP3A activity in cancer patients have been performed using exogenous probes, e.g., oral, or intravenous midazolam or erythromycin breath test [ 8 , 9 ]. Results have been conflicting.…”

“…Results have been conflicting. One study demonstrated a reduction in CYP3A activity by 40% in cancer patients compared to healthy volunteers, while another study in Asian cancer patients compared to non-cancer patients did not find any differences [ 8 , 39 ].…”

“…Phenotyping studies on CYP3A metabolism in palliative cancer patients have usually been performed using exogenous probes. Studies evaluating the CYP3A activity using midazolam or erythromycin breath test in cancer patients have shown reduced enzymatic activity compared to healthy volunteers [ 8 , 9 ]. However, the subjects in these studies with advanced, non-curable cancer had normal BMI and did not suffer from cachexia or organ failure; common denominators in end-of-life patients [ 10 , 11 ].…”