Alfentanil-Induced Miosis as a Surrogate Measure of Alfentanil Pharmacokinetics in Patients with Mild and Moderate Liver Cirrhosis

Abstract

Alfentanil pharmacokinetic parameters were correlated with miosis pseudo-kinetic parameters in cirrhotic patients. There was a significant decrease in pharmacokinetics and miosis pseudo-kinetics in cirrhotic patients compared with volunteers from the historical control group. Alfentanil-induced miosis has the advantage of being noninvasive and can be limited to miosis measurements during the first 2 hours after alfentanil administration in cirrhotic patients. We thus propose to substitute the AUC(2(miosis)) for alfentanil pharmacokinetics in cirrhosis.

Physiologically Based Pharmacokinetic Modeling for Olaparib Dosing Recommendations: Bridging Formulations, Drug Interactions, and Patient Populations

“…The reduced CYP3A abundance in patients with hepatic impairment is supported by clinical studies investigating the pharmacokinetics of CYP3A4 substrates (alprazolam, alfentanil, midazolam, rivaroxaban), which included plasma protein-binding measurements and cohorts of patients with hepatic impairment compared with healthy age-matched subjects. [30][31][32] There are several drugs predominantly metabolized by CYP3A that have little change in drug exposure when given to patients with hepatic impairment (e.g., doravirinin, bosutinib, ombitasvir, ritonavir) 33 ; the studies reported here show that olaparib appears to behave in a similar manner. Finally, the tablet model was used to predict the exposure to olaparib when given to pediatric subjects of different ages by accounting for the ontogeny of the CYP enzymes.…”

“…The decrease in olaparib absorption observed appeared to counteract the effect of metabolism decrease, resulting in little change in the exposure of olaparib in patients with moderate hepatic impairment. The reduced CYP3A abundance in patients with hepatic impairment is supported by clinical studies investigating the pharmacokinetics of CYP3A4 substrates (alprazolam, alfentanil, midazolam, rivaroxaban), which included plasma protein‐binding measurements and cohorts of patients with hepatic impairment compared with healthy age‐matched subjects . There are several drugs predominantly metabolized by CYP3A that have little change in drug exposure when given to patients with hepatic impairment (e.g., doravirinin, bosutinib, ombitasvir, ritonavir); the studies reported here show that olaparib appears to behave in a similar manner.…”

Brivaracetam Disposition in Mild to Severe Hepatic Impairment

“…Antipyrine, a marker for CYP‐mediated metabolism, was given orally at a dose of 600 mg. Saliva samples (minimum 2 mL) were collected before and 0.5, 1, 2, 4, 6, 8, 10, 12, 24, 36, and 48 hours after antipyrine intake. D‐sorbitol non‐renal clearance and antipyrine clearance were computed as described previously …”

“…The concentration of D‐sorbitol in plasma and in urine was measured by the sorbitol dehydrogenase enzyme‐UV method and antipyrine was determined in saliva by HPLC‐UV, as described previously …”

“…D-sorbitol non-renal clearance and antipyrine clearance were computed as described previously. 19 Following successful completion of the dynamic liver function tests described above, participants were admitted to the study center 24 hours before dosing and administered a single 100 mg dose of brivaracetam taken with 240 mL of water after an overnight fast and remained in the center for the first 96 hours post-dose. Blood samples for brivaracetam and metabolite (acid, hydroxy, and hydroxyacid) assay were collected in sodium heparin tubes before and at 0.5, 1, 1.5, 2, 3, 4, 6, 9, 12, 24, 36, 48, 60, 72, 84, and 96 hours after dosing.…”