John T. Callaghan

QT effects of duloxetine at supratherapeutic doses: A placebo and positive controlled study

Background: The electrophysiological effects of duloxetine at supratherapeutic exposures were evaluated to ensure compliance with regulatory criteria and to assess the QT prolongation potential. Methods: Electrocardiograms were collected in a multicenter, double-blind, randomized, placebo-controlled, crossover study that enrolled 117 healthy female subjects aged 19 to 74 years. Duloxetine dosages escalated from 60 mg twice daily to 200 mg twice daily; a single moxifloxacin 400 mg dose was used as a positive control. Data were analyzed using 3 QT interval correction methods: mixed-effect analysis of covariance model with RR interval change from baseline as the covariate, the QT Fridericias correction method, and the individual QT correction method. Concentrations of duloxetine and its 2 major metabolites were measured. Results: Compared with placebo, the mean change from baseline in QTc decreased with duloxetine 200 mg twice daily. The upper limits of the 2-sided 90% confidence intervals for duloxetine vs. placebo were <0 msec at each time point by any correction method. No subject had absolute QT Fridericias correction values >445 msec with duloxetine, and the change in QT Fridericias correction from baseline with duloxetine did not exceed 36 msec. No relationship was detected between QTc change and plasma concentrations of duloxetine or its metabolites even though average duloxetine concentrations ranged to more than 5 times those achieved at therapeutic doses. Moxifloxacin significantly prolonged QTc at all time points, regardless of correction method. Conclusions: Duloxetine does not affect ventricular repolarization as assessed by both mean changes and outliers in QT corrected by any method.

Olanzapine: Interaction study with imipramine

Olanzapine is an “atypical” antipsychotic agent with a high affinity for serotonin 5HT2A/C, 5HT3, 5HT6, and dopamine D1, D2, D3, D4 receptors. Depressed patients with psychotic disorders frequently require treatment with concomitant antipsychotic and antidepressant medications. Imipramine pharmacokinetics serve as a marker for hepatic CYP2D6, CYP1A2, CYP3A activity. An open‐label, three‐way randomized crossover study was done to determine the safety, pharmacokinetics, and potential for a drug interaction between olanzapine (5 mg) and imipramine (75 mg). Each drug was administered alone and in combination. Nine healthy men, ages 32 to 54 years, enrolled in the study. Psychomotor performance capacities, plasma olanzapine, imipramine, desipramine concentrations, and clinical laboratory tests were measured. Pharmacokinetic variables, vital signs, subjective tests for liveliness, and psychomotor outcomes were analyzed using a two‐way ANOVA. Olanzapine was safe. Sedation, postural hypotension, and minor vital sign alterations occurred during all treatments. On the liveliness questionnaire, patients generally reported poorer (less lively) scores with olanzapine alone or coadministered with imipramine versus baseline scores. These effects disappeared within 24 hours after administration. Olanzapine alone and in combination decreased motor‐speed tasks (finger tapping and visual‐arm random reach) compared with baseline or imipramine treatment. Peak 6‐hour changes were statistically significant but clinical importance was only marginal. Olanzapine concentrations were <19% greater than with imipramine. But olanzapine did not affect the kinetics of imipramine or desipramine and, therefore, did not show a metabolic drug interaction involving CYP2D6. J Clin Pharmacol 1997;37:971–978.

Absorption studies of the H2‐blocker nizatidine

The absolute and relative bioavailability of nizatidine, an H2‐blocker, was studied in healthy male volunteers. The absolute oral bioavailability, relative to that after intravenous administration, was 98% ± 14%. The bioavailability of single and multiple oral doses of 150 mg nizatidine was unaffected by concurrent food ingestion; nizatidine may be administered either with or without food. The relative bioavailability of nizatidine was compared when given simultaneously with placebo or Gelusil, 30 minutes after propantheline, or 60 minutes before activated charcoal. Gelusil reduced the amount of nizatidine absorbed by about 10%, charcoal reduced it by about 30%, and propantheline did not affect it.

Secretion of nizatidine into human breast milk after single and multiple doses.

Disposition of the H2‐receptor antagonist nizatidine was studied in serum, urine, and breast milk. Five lactating women and five nonlactating women participated; the disposition of nizatidine was studied in three of the lactating women. Single and multiple doses of 150 mg nizatidine were administered orally. The disposition of nizatidine (half‐life, 1½ hours; apparent serum clearance, 40 L/hr; renal clearance, 27 L/hr; and apparent volume of distribution, 1.4 L/kg) was similar in lactating and nonlactating women. These pharmacokinetic results were analogous to observations for men in other studies. Nizatidine breast milk concentrations were directly proportional to corresponding serum concentrations. On average, 96 μg nizatidine, less than 0.1% of the maternal dose, was secreted into milk during a 12‐hour interval after either single or multiple doses.

Nizatidine, an H2‐Receptor Antagonist: Disposition and Safety in the Elderly

Nizatidine is an orally active H2‐receptor blocker. Its disposition and safety in eight young and 12 elderly volunteers were investigated. Single oral doses of nizatidine were administered: from 100 mg to 300 mg in the elderly, and from 100 mg to 350 mg in the young. The nizatidine AUC was directly proportional to dose for both groups. Calculated pharmacokinetic variables in the elderly vs. the young were t1/2 = 1.9 vs. 1.6 hr; CLp/f = 32 vs. 40 L/hr, and Vdβ/f = 1.2 vs. 1.3 L/kg. The impaired renal function of some elderly volunteers prolonged nizatidine elimination and lowered its clearance. Renal impairment rather than advanced age per se was the predominant factor in decreasing the nizatidine elimination rate. Because Clcr correlated directly with nizatidine renal clearance, Clcr values may be used to estimate nizatidine dosage reductions in renal insufficiency. During the trial, no serious adverse effects occurred.

Lack of Effect of Olanzapine on the Pharmacokinetics of a Single Aminophylline Dose in Healthy Men

Study Objective. To test whether olanzapine, an atypical antipsychotic, is an inhibitor of cytochrome P450 (CYP) 1A2 activity, we conducted a drug interaction study with theophylline, a known CYP1A2 substrate.

Pharmacogenetic testing in the Veterans Health Administration (VHA): policy recommendations from the VHA Clinical Pharmacogenetics Subcommittee

PurposeThe Veterans Health Administration (VHA) Clinical Pharmacogenetics Subcommittee is charged with making recommendations about whether specific pharmacogenetic tests should be used in healthcare at VHA facilities. We describe a process to inform VHA pharmacogenetic testing policy.MethodsAfter developing consensus definitions of clinical validity and utility, the Subcommittee identified salient drug–gene pairs with potential clinical application in VHA. Members met monthly to discuss each drug–gene pair, the evidence of clinical utility for the associated pharmacogenetic test, and any VHA-specific testing considerations. The Subcommittee classified each test as strongly recommended, recommended, or not routinely recommended before drug initiation.ResultsOf 30 drug–gene pair tests reviewed, the Subcommittee classified 4 (13%) as strongly recommended, including HLA-B*15:02 for carbamazepine-associated Stevens–Johnston syndrome and G6PD for rasburicase-associated hemolytic anemia; 12 (40%) as recommended, including CYP2D6 for codeine toxicity; and 14 (47%) as not routinely recommended, such as CYP2C19 for clopidogrel dosing.ConclusionOnly half of drug–gene pairs with high clinical validity received Subcommittee support for policy promoting their widespread use across VHA. The Subcommittee generally found insufficient evidence of clinical utility or available, effective alternative strategies for the remainders. Continual evidence review and rigorous outcomes research will help promote the translation of pharmacogenetic discovery to healthcare.