Pharmacokinetics Of Midazolam In Patients Research Articles

Abstract B218: Drug-drug interaction assessment of GDC-0032, a beta-sparing inhibitor of phosphoinositide 3-kinase (PI3K), using midazolam, a sensitive CYP3A4 substrate.

Abstract Background: GDC-0032 is an orally-bioavailable, potent, and selective inhibitor of Class IA PI3K alpha, delta, gamma, and p110 beta isoforms, with 30 fold less inhibition of the p110 beta isoform. GDC-0032 has shown promising preliminary clinical activity in PIK3CA-mutant cancers and is being explored in solid tumors and in combination with endocrine therapies in breast cancer. In vitro, GDC 0032 was not a potent inhibitor of CYP isoforms 1A2, 2B6, 2C8, 2C9, 2C19, 2D6, or 3A4 (IC50 > 30 µM) but displayed weak time-dependent inhibition of CYP3A4, with KI and kinact values of 77 µM and 0.030 min-1, respectively. In addition, GDC-0032 induced CYP3A4, but not CYP1A2 or CYP2B6 in human hepatocytes. Based on these data, the potential for GDC-0032 to impact the pharmacokinetics (PK) of midazolam (MDZ), a sensitive in vivo marker of CYP3A4 enzymatic activity, was assessed in a Phase I trial in patients with cancer. Methods: Twelve patients with advanced or metastatic solid tumors were enrolled. All patients received 5 mg MDZ on Day 1 (D1), followed by continuous daily dosing of GDC-0032 (9 mg) starting on D2. A second MDZ dose was given on D16. Predose, 0.5, 1, 1.5, 2, 3, 4, 8, and 24 hr post-dose plasma samples were collected on D1 and D16. Maximum concentration (Cmax) and area under the concentration-time curve (AUC0-24) of MDZ were estimated by non-compartmental methods using WinNonlin (version 5.2.1). MDZ plasma Cmax and AUC0-24 without GDC-0032 (D1) and after 15 daily doses of GDC-0032 (D16) were compared. The geometric mean ratios (GMRs) of Cmax and AUC0-24 and the corresponding 90% CIs were estimated (WinNonlin version 5.2.1). Physiologically-Based Pharmacokinetic (PBPK) modeling was used to prospectively predict the DDI potential of GDC-0032 (Simcyp version 11.0 and Gastroplus version 8.0). Results: No trend in individual Cmax or AUC0-24 of MDZ was observed post-GDC-0032 treatment relative to pre-treatment. The change in MDZ exposure (Cmax and AUC0-24) before and after GDC-0032 treatment was less than 2-fold for all patients (median: 1.1 fold; range: 0.4-1.9). The GMRs (90% CIs) for MDZ+GDC-0032 relative to MDZ alone for Cmax and AUC0-24 were 0.98 (0.70-1.37) and 1.04 (0.68-1.60), respectively. Prospective PBPK modeling accurately predicted a lack of marked DDI between GDC-0032 and MDZ (1-1.4 fold change). Conclusions: Despite in vitro results suggesting that GDC-0032 may impact the PK of concomitant medications which are metabolized by CYP3A4, co-administration with MDZ did not change the PK of MDZ in patients with cancer. PBPK modeling predicted little to no impact of GDC-0032 on the PK of MDZ, consistent with the in vivo observation. These results indicate that GDC-0032 may be given concomitantly with CYP substrates with minimal risk of a PK drug-drug interaction. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B218. Citation Format: Richard A. Graham, Sravanthi Cheeti, Laurent Salphati, Tong Lu, Carla Kurkjian, Daniel Von Hoff, Jasgit Sachdev, Dejan Juric, Jose Baselga, Hema Parmer, Jerry Hsu, Jeffrey Infante. Drug-drug interaction assessment of GDC-0032, a beta-sparing inhibitor of phosphoinositide 3-kinase (PI3K), using midazolam, a sensitive CYP3A4 substrate. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr B218.

Clinical Pharmacokinetics, Metabolism, and Drug-Drug Interaction of Carfilzomib

Carfilzomib, an irreversible proteasome inhibitor, has a favorable safety profile and significant antitumor activity in patients with relapsed and refractory multiple myeloma (MM). Here we summarize the clinical pharmacokinetics (PK), metabolism, and drug-drug interaction (DDI) profile of carfilzomib. The PK of carfilzomib, infused over 2-10 minutes, was evaluated in patients with solid tumors or MM. Metabolites of carfilzomib were characterized in patient plasma and urine samples. In vitro drug metabolism and DDI studies were conducted in human liver microsomes and hepatocytes. A clinical DDI study was conducted in patients with solid tumors to evaluate the effect of carfilzomib on CYP3A activity. Plasma concentrations of carfilzomib declined rapidly and in a biphasic manner after intravenous administration. The systemic half-life was short and the systemic clearance rate was higher than hepatic blood flow. Carfilzomib was cleared largely extrahepatically via peptidase cleavage and epoxide hydrolysis. Cytochrome P450-mediated metabolism played a minor role, suggesting that coadministration of P450 inhibitors or inducers is unlikely to change its PK profile. Carfilzomib showed direct and time-dependent inhibition of CYP3A in human liver microsome preparations and exposure to carfilzomib resulted in reductions in CYP3A and 1A2 gene expression in cultured human hepatocytes. However, administration of carfilzomib did not affect the PK of midazolam in patients with solid tumors, and there were no safety signals indicative of potential drug interactions. We conclude that the rapid systemic clearance and short half-life of carfilzomib limit clinically significant DDI.

I.v. fentanyl decreases the clearance of midazolam

We have examined the effect of fentanyl on the pharmacokinetics of midazolam in patients undergoing orthopaedic surgery. Thirty patients were allocated randomly to receive fentanyl 200 micrograms and midazolam 0.2 mg kg-1 (fentanyl group, n = 15) or placebo and midazolam 0.2 mg kg-1 (placebo group, n = 15) in a double-blind manner for induction of anaesthesia. Anaesthesia was maintained with nitrous oxide and isoflurane. Systemic clearance of midazolam was decreased by 30% (P = 0.002) and elimination half-time was prolonged by 50% (P = 0.04) in the fentanyl group compared with the placebo group. There were no differences in the distribution half-time or volume of distribution at steady state between the two groups. These findings indicate that elimination of midazolam was inhibited by fentanyl during general anaesthesia.

Pharmacokinetics of Midazolam in Patients Recovering from Cardiac Surgery

Department of Anesthesiology and Department of Clinical Pharmacology and Department of Internal Medicine, University of Basel, Basel, Switzerland

The pharmacokinetics of midazolam in patients with congestive heart failure.

The disposition of midazolam was investigated in six patients with congestive heart failure (CHF) and six age- and weight-matched healthy subjects by administering two single doses of the drug (3.75 mg i.v. and 7.5 mg p.o.) separated by 1 week. Serial blood samples were collected for 24 h after each dose and plasma was assayed for midazolam by GC-MS. In the CHF patients, the elimination half-life was prolonged (4 to 4.5 vs less than 3 h), the systemic clearance was lowered (376 vs 551 ml min-1) and the peak plasma drug concentration after the p.o. dose was higher (76 vs 42 ng ml-1). The systemic availability (45 vs 41%), the steady state volume of distribution (111 vs 108 l) and the time of peak plasma drug concentration after the p.o. dose (0.9 vs 0.9 h) were unchanged. The predominant effect of CHF was on the clearance of midazolam which was decreased by 30%. The drug was well tolerated and did not cause any adverse effects.

Pharmacokinetics of midazolam in patients recovering from cardiac surgery.

The pharmacokinetics of midazolam has been studied in patients recovering from cardiac surgery, who required sedation for postoperative mechanical ventilation. Twelve males (mean age 64.5 years) with severe heart disease received an infusion of midazolam 15 mg.h-1 for 4 h, starting 1 to 3 h post surgery. Multiple blood samples were collected from each patient during the infusion and up to 48-93 h after it. The pharmacokinetic parameters of midazolam were determined using both moment analysis and the program NONMEM. The average terminal half-life was 10.6 h. The prolonged elimination was mainly due to a decrease in its metabolic clearance (0.25 l.min-1). The maintenance infusion dose of midazolam in such patients should be reduced. The time to recovery after stopping an infusion depends upon the amount of drug in the body at that time and a simulation of the plasma concentrations after various infusion regimens suggests that recovery will be delayed after prolonged (greater than 48 h) administration of midazolam to these patients. However, after shorter infusions (less than 12 h), redistribution of the drug away from the site of action was still occurring and recovery would be expected to be relatively rapid.