Search results for "PHARMACOKINETICS"
showing 10 items of 458 documents
The role of cytochrome P450 2D6 in the metabolism of moclobemide.
1996
The metabolic fate of moclobemide (Ro 11-1163), a new reversible and selective inhibitor of monoamine oxidase type A (MAO-A), has been assessed in a pilot study in 2 debrisoquine poor metabolizers (PM) and 4 extensive metabolizers (EM) after multiple oral dosings of moclobemide with and without co-medication of dextromethorphan. Absorption and disposition parameters were not different between PM and EM. Concurrent application of dextromethorphan, a selective substrate of CYP2D6, did not affect the pharmacokinetics of moclobemide. These results indicate that the cytochromal isoenzyme CYP2D6 does not play a major role in the metabolic degradation of moclobemide. Limited CYP2D6 activities beca…
A phase I pharmacokinetic and pharmacodynamic study of dalotuzumab (MK-0646), an anti-insulin-like growth factor-1 receptor monoclonal antibody, in p…
2011
Abstract Purpose: Insulin-like growth factor-1 receptor (IGF-1R) mediates cellular processes in cancer and has been proposed as a therapeutic target. Dalotuzumab (MK-0646) is a humanized IgG1 monoclonal antibody that binds to IGF-1R preventing receptor activation. This study was designed to evaluate the safety and tolerability of dalotuzumab, determine the pharmacokinetic (PK) and pharmacodynamic (PD) profiles, and identify a recommended phase II dose. Experimental Design: Patients with tumors expressing IGF-1R protein were allocated to dose-escalating cohorts of three or more patients each and received intravenous dalotuzumab weekly, every 2 or 3 weeks. Plasma was collected for PK analysis…
Phase I Pharmacokinetic/Pharmacodynamic Study of MLN8237, an Investigational, Oral, Selective Aurora A Kinase Inhibitor, in Patients with Advanced So…
2012
Abstract Purpose: Aurora A kinase (AAK) is a key regulator of mitosis and a target for anticancer drug development. This phase I study investigated the safety, pharmacokinetics, and pharmacodynamics of MLN8237 (alisertib), an investigational, oral, selective AAK inhibitor, in 59 adults with advanced solid tumors. Experimental Design: Patients received MLN8237 once daily or twice daily for 7, 14, or 21 consecutive days, followed by 14 days recovery, in 21-, 28-, or 35-day cycles. Dose-limiting toxicities (DLT) and the maximum-tolerated dose (MTD) for the 7- and 21-day schedules were determined. Pharmacokinetic parameters were derived from plasma concentration–time profiles. AAK inhibition in…
Phase I Pharmacokinetic and Pharmacodynamic Dose-Escalation Study of RG7160 (GA201), the First Glycoengineered Monoclonal Antibody Against the Epider…
2011
Purpose We conducted a phase I dose-escalation study to characterize the safety, efficacy, pharmacokinetic (PK), and pharmacodynamic properties of RG7160 (GA201), a humanized and glycoengineered immunoglobulin G1 anti–epidermal growth factor receptor (EGFR) monoclonal antibody with enhanced antibody-dependent cell-mediated cytotoxicity. Patients and Methods Seventy-five patients with advanced EGFR-positive solid tumors received RG7160 (50 to 1,400 mg) administered every week, every 2 weeks, or every 3 weeks. Dose escalation followed a three-plus-three trial design. Results No maximum-tolerated dose was reached for any dosing schedule. Common adverse events (AEs) included rash (80% of patien…
New levothyroxine formulation meeting 95–105% specification over the whole shelf-life: results from two pharmacokinetic trials
2016
Small levothyroxine (L-T4) dose changes can lead to significant clinical effects. To ensure thyroid hormone levels are safely maintained, authorities are increasingly adopting stricter potency specifications for L-T4, the most stringent of these being 95-105% of the labeled dose over the whole shelf-life. Levothyroxine sodium (Euthyrox, Eutirox, Lévothyrox ) has been reformulated, and two studies performed, to ensure bioequivalence to the currently marketed formulation and dosage form proportionality of the new formulation.The bioequivalence study was an open-label, randomized, single-dose, two-period, two-sequence crossover comparing the highest dosage strengths of the currently marketed a…
Expanded gentamicin volume of distribution in critically ill adult patients receiving total parenteral nutrition
1995
Aminoglycoside antibiotics distribute into the extracellular fluid compartment and are eliminated by the kidney via glomerular filtration. Malnutrition and total parenteral nutrition influence the fluid and electrolyte status of the patient, and cause organ changes. The purpose of this clinical study was to characterize the kinetic behaviour of gentamicin in the parenterally fed critically ill adult patient. Eighty-six critically ill adult patients treated with gentamicin for severe Gram-negative infections were enrolled in the study (mean +/- SD): age, 60 +/- 14 years; weight, 69.4 +/- 10.2 kg; height, 163 +/- 10 cm; 22 females and 64 males. Four study groups were defined (2 x 2): total pa…
Relationship between rheological properties, in vitro release and in vivo equivalency of topical formulations of diclofenac.
2019
Determination of bioequivalence remains a challenge in generic topical drug development. To support pharmacokinetic studies, strategies to demonstrate microstructure sameness of the products being compared include in vitro evaluations, such as the comparison of rheological properties, droplet size and in vitro release rates. Nevertheless, defining the appropriate acceptance range to consider equivalence between test and reference formulation is complex. To shed more light into this issue, in vitro release and rheological properties were compared to in vivo bioequivalence data (systemic blood measurements within a clinical trial) after topical application of a single dose. Test and reference…
Pharmacokinetic analysis of the interaction between dicoumarol and tolbutamide in man
1976
The effect of repeated administration of tolbutamide on the elimination and anticoagulant action of a single oral dose of dicoumarol 600 mg was studied in four healthy male subjects using a crossover design. In all subjects the plasma concentration of dicoumarol in the postabsorptive phase was lower during concomitant tolbutamide treatment. However, the subjects differed with respect to the elimination kinetics of dicoumarol and the effect of tolbutamide on some of the measured pharmacokinetic paramaters. In two subjects dicoumarol was eliminated by apparent first-order kinetics. Tolbutamide led to a pronounced increase in the elimination rate and a shift in the plasma concentration-respons…
Justification of Biowaiver for Carbamazepine, a Low Soluble High Permeable Compound, in Solid Dosage Forms Based on IVIVC and Gastrointestinal Simula…
2009
The aim of the present study was to use gastrointestinal simulation technology and in vitro-in vivo correlation (IVIVC) as tools to investigate a possible extension of biowaiver criteria to BCS class II drugs using carbamazepine (CBZ) as a candidate compound. Gastrointestinal simulation based on the advanced compartmental absorption and transit model implemented in GastroPlus was used. Actual in vitro and in vivo data generated in CBZ bioequivalence studies were used for correlation purposes. The simulated plasma profile, based on the CBZ physicochemical and pharmacokinetic properties, was almost identical with that observed in vivo. Parameter sensitivity analysis (PSA) indicated that the p…
A novel technique for intraduodenal administration of drug suspensions/solutions with concurrent pH monitoring applied to ibuprofen formulations
2019
Characterization of dissolution of solid suspended drug particles in vivo is important for developing biopredictive in vitro tests. Therefore, methods to gain deeper insights into particle dissolution in vivo are needed. The soft Bioperm intubation method, a well established tool for investigation of permeability, absorption, metabolism, and drug interactions at predefined locations in the gastroinstinal tract, was modified. The novel intubation method involved pump-controlled infusion of pharmaceutical suspensions as well as simultaneous pH monitoring. This technique was used in a proof of concept study in healthy humans. Plasma sampling and non-compartmental analysis allowed comparison of…