Edward J. Antal

PHARMACOKINETIC PHARMACODYNAMIC EVALUATION OF THE COMBINED ADMINISTRATION OF ALPRAZOLAM AND FLUOXETINE

The pharmacokinetic and pharmacodynamic effects of concomitant administration of alprazolam and fluoxetine were studied in this double-blind parallel study in 80 healthy, male volunteers. Subjects were randomly assigned to one of four treatment groups. Drug treatments consisted of 4-day regimens of 1 mg alprazolam four times daily, 60 mg fluoxetine every morning, 1 mg alprazolam four times daily and 60 mg fluoxetine every morning, and placebo four times daily. Psychomotor performance, mood status, and degree of sedation were evaluated at designated times. Combined administration of alprazolam and fluoxetine resulted in an approximate 30% increase in plasma alprazolam concentrations relative to plasma concentrations following the administration of alprazolam alone. There were no significant differences in fluoxetine or norfluoxetine plasma concentrations between the alprazolam/fluoxetine and fluoxetine treatments. Psychomotor decrements increased when fluoxetine was administered with alprazolam relative to alprazolam administration alone. Psychomotor performance of the fluoxetine treatment group was not significantly different from that of the placebo group. No significant changes were observed in mood status, and sedation was minimal in all treatment groups. As when any two psychoactive drugs are administered together, increased patient monitoring and patient education is recommended when alprazolam and fluoxetine are prescribed concurrently.

Linezolid: Pharmacokinetic and Pharmacodynamic Evaluation of Coadministration with Pseudoephedrine HCl, Phenylpropanolamine HCl, and Dextromethorphan HBr

Linezolid is a novel oxazolidinone antibiotic with mild reversible monoamine oxidase inhibitor (MAOI) activity. The potential for interaction with over‐the‐counter (OTC) medications requires quantification. The authors present data evaluating the pharmacokinetic and pharmacodynamic responses to coadministration of oral linezolid with sympathomimetics (pseudoephedrine and phenylpropanolamine) and a serotonin reuptake inhibitor (dextromethorphan). Following coadministration with linezolid, minimal but statistically significant increases were observed in pseudoephedrine and phenylpropanolamine plasma concentrations; a minimal but statistically significant decrease was observed in dextrorphan (the primary metabolite of dextromethorphan) plasma concentrations. Increased blood pressure (BP) was observed following the coadministration of linezolid with either pseudoephedrine or phenylpropanolamine; no significant effects were observed with dextromethorphan. None of these coadministered drugs had a significant effect on linezolid pharmacokinetics. Minimal numbers of adverse events were reported. Potentiation of sympathomimetic activity by linezolid was judged not to be clinically significant, but patients sensitive to the effects of increased BP due to predisposing factors should be treated cautiously. No restrictions are indicated for the coadministration of dextromethorphan and linezolid.

Comparison of alprazolam plasma levels in normal Asian and Caucasian male volunteers

Single-dose pharmacokinetics of alprazolam was studied in 42 normal male volunteers (14 Caucasians, 14 American-born Asians, and 14 foreign-born Asians), after both oral and parenteral (IV) administration of a small dose (0.5 mg) of the test drug. Asians manifested significantly higher Cmax, larger AUC, slower CL and longer t 1/2 under both testing situations. When body surface area was used as a covariate, these cross-ethnic differences remained statistically significant (except Cmax) after oral but not IV drug administration. There were no differences between the two Asian groups in any of these parameters examined in this study. These results confirmed previous observations of ethnic differences in the pharmacokinetic response between Asians and Caucasians and suggested that smaller doses of alprazolam may be required for Asians for similar clinical effects as compared to their Caucasian counterparts.

An evaluation of population pharmacokinetics in therapeutic trials. Part II. Detection of a drug-drug interaction.

The use of observational data, collected during the routine clinical care of patients, has been advocated as a means to obtain clinically relevant information regarding the pharmacokinetic parameters of drugs. However, the validity of this approach and its proper role in new drug development is unclear. This study was performed to evaluate the ability of three approaches to estimate population pharmacokinetic parameters: the traditional approach, mixed‐effect modeling, and a simple pharmacokinetic screen. The evaluation was performed with data collected during a multicenter, open‐label study evaluating the efficacy, safety, and pharmacokinetics of imipramine and alprazolam in combination. The traditional pharmacokinetic study demonstrated a 20% decrease in the clearance of imipramine in the presence of 4 mg/day alprazolam. Mixed‐effect modeling extends these findings by suggesting that the interaction is dependent on the simultaneous concentration of alprazolam, a finding that was not possible under the study design typically used for traditional pharmacokinetic studies. Although the simple screen suggests the presence of the drug‐drug interaction, limited information regarding pharmacokinetic parameters is available and those parameters that can be estimated are biased.

Linezolid, a novel oxazolidinone antibiotic: assessment of monoamine oxidase inhibition using pressor response to oral tyramine.

The primary objective of this study was to compare the effects of oral linezolid with moclobemide and placebo on the pressor response to oral tyramine. Secondary objectives were to determine possible mechanisms of the effect based on changes in the pharmacokinetics of tyramine and to evaluate alternative methods for quantifying the pressor effect. Subjects received linezolid (625 mg bid orally), moclobemide (150 mg tid orally), or placebo for up to 7 days. Using the oral tyramine dose producing a > 30 mmHg increase in systolic blood pressure (SBP) (PD>30), a positive pressor response was defined as a PD> 30 index (pretreatment/treatment ratio of PD> 30) of ≥ 2. There were 8/10, 11/11, and 1/10 responders with linezolid, moclobemide, and placebo, respectively. Responses returned to baseline within 2 days of drug discontinuation. The ratio of mean greatest SBP and heart rate at the time of greatest SBP (GSBP/HR) increased linearly with tyramine dose both pretreatment and during treatment with linezolid and moclobemide. During treatment, responses to tyramine when subjects took linezolid or moclobemide were significantly different from placebo. Both drugs significantly decreased tyramine oral clearance compared with placebo. Urinary excretion of catecholamines and metabolites was consistent with MAOI activity of the drugs, but results were variable. The MAOI activity of linezolid is similar to that of moclobemide, a drug used clinically without food restrictions. Restrictions to normal dietary intake of tyramine‐containing foods are not warranted when taking linezolid.

CYP3A and P-glycoprotein activity induction with St. John's Wort in healthy volunteers from 6 ethnic populations.

I has been reported that St. John’s Wort (SJW) may have inducing effects on the cytochrome P450 enzyme system, specifically the CYP3A4 isoform (CYP3A4) and the intestinal P-glycoprotein (Pgp) efflux membrane transporter. This may have profound implications on patients taking medications that are substrates for Pgp and/or CYP3A4. Ethnic difference is an important factor to determine drug metabolism and response. Varying results have been reported in studies evaluating ethnic differences in the pharmacokinetic disposition of Pgp/CYP3A4 substrates and suggest that these differences may be attributed to ethnically associated differences in intestinal Pgp and CYP3A4 activity. Fexofenadine and midazolam have been widely used as probes for intestinal and hepatic Pgp transporter and CYP3A enzyme activities in human interaction studies. In vivo studies examining SJW induction on CYP3A4 and Pgp substrates’ pharmacokinetic (PK) parameters and its relationship among various ethnic groups have not been examined extensively. The purpose of the current study was to investigate whether any differences in the inducibility of Pgp and CYP3A by SJW are present among 6 ethnic groups in healthy volunteers using fexofenadine and midazolam as probes.

Influence of route of administration on the pharmacokinetics of methylprednisolone

This study was conducted to evaluate the influence of route of administration upon the bioavailability and pharmacokinetics of methylprednisolone sodium succinate. Fourteen healthy adult male volunteers received 40 mg doses of methylprednisolone as the following treatments after an overnight fast in a 4-way crossover design: (a) as a 1 ml i.v. bolus;(b) as a 1 ml i.m. injection;(c) administered as an oral solution;and (d) as 5×8 mg oral tablets. Both the ester and free methylprednisolone were determined in plasma and urine. Study results indicate that the ester is rapidly and extensively converted to free methylprednisolone after all routes. The extent of methylprednisolone absorption was equivalent after i.v. and i.m. administration. Both orally administered treatments resulted in a lower extent of absorption attributed to a first-pass effect. Although a slightly lower extent of absorption was demonstrated following the oral administration of the methylprednisolone sodium succinate solution relative to the methylprednisolone oral tablets, this average difference of 9% would probably be of minimal therapeutic importance.

Effects of Aspirin and Ibuprofen on the Pharmacokinetics and Pharmacodynamics of Glyburide in Healthy Subjects

OBJECTIVE: To determine the effects of aspirin and ibuprofen on the pharmacokinetics and pharmacodynamics of glyburide in healthy volunteers. DESIGN: Single-center, randomized, two-way, crossover design following an initial baseline evaluation phase. SETTING: Outpatient, university-based ambulatory care facility. PATIENTS: Sixteen healthy nonsmoking men aged 20–34 years. INTERVENTION: Three phases consisting of six treatments. Phase 1 began with treatment A, a baseline oral glucose tolerance test (GTT), followed by treatment B, glyburide 5 mg plus a GTT. The other two phases were administered in a crossover design. Phase 2 consisted of the administration of aspirin 975 mg qid for 4 days. On day 3 a GTT was administered (treatment C) and on day 4 glyburide 5 mg plus a GTT was administered (treatment E). Phase 3 consisted of the administration of ibuprofen 600 mg qid for 4 days with a GTT on day 3 (treatment D) and glyburide 5 mg plus a GTT on day 4 (treatment F). MAIN OUTCOME MEASURES: Serum glyburide concentrations after each treatment, as well as glucose and insulin, ibuprofen, and salicylate serum concentrations and glyburide free fractions. RESULTS: Aspirin administration resulted in an 85% increase in mean total glyburide oral clearance and a 29% increase in glyburide free fraction. Ibuprofen administration resulted in a slight increase in mean glyburide free fraction, but no significant changes in glyburide pharmacokinetic parameters were observed. Insulin concentrations were increased during the glyburide plus aspirin treatment. Conflicting results were observed in the glucose parameters. CONCLUSIONS: The potential for this glyburide—aspirin interaction resulting in a transient hypoglycemia should be considered in diabetic patients receiving glyburide therapy.

The Influence of Hemodialysis on the Pharmacokinetics of Ibuprofen and Its Major Metabolites

The pharmacokinetics of ibuprofen and its two major metabolites, the hydroxy and carboxy derivatives, were studied in seven functionally anephric subjects undergoing hemodialysis therapy. Subjects received ibuprofen 800 mg tid for 14 days. Hemodialysis was performed three times weekly during this period. Arterial and venous blood samples were collected before dialysis and along with dialysate, and during the final dosing interval and dialysis session. No accumulation of ibuprofen plasma concentrations and an absence of intact ibuprofen in dialysate indicated clearance through metabolic pathways. The metabolites did accumulate significantly (mean plasma levels, carboxy 249 μg/mL and hydroxy 57 μ/mL); however, both were detected in dialysate. Mean extraction efficiencies were 0.16 (hydroxy) and 0.15 (carboxy). Dialysis clearance calculated by arterial‐venous difference was found to agree with actual recovery in dialysate for both metabolites. Side effects were not observed in any subject.

Comparison of Pharmacokinetics and Pharmacodynamics of Short- and Long-Term Glyburide Therapy in NIDDM

OBJECTIVE To examine the pharmacokinetics and pharmacodynamics of glyburide after single- and multiple-dose administration in patients with type II diabetes. RESEARCH DESIGN AND METHODS Twenty patients with type II diabetes between 40 and 70 years of age participated in the study. A 24-h pharmacokinetic evaluation including a 4-h Sustacal tolerance test was conducted before instituting glyburide therapy (baseline), after the first 2.5-mg test dose of glyburide and at weeks 6 and 12 of chronic glyburide therapy. Glyburide doses were titrated with a target goal of achieving a fasting plasma glucose of ≤ 7.8 mmol/l or to reach maximum daily doses of 20 mg. RESULTS A significant prolongation in the elimination half-life (t1/2: week 0, 4.0 ± 1.9 h; week 6, 13.7 ± 10.5 h; and week 12, 12.1 ± 8.2 h) and an increased volume of distribution of glyburide was observed during chronic dosing. These results strongly suggest possible drug accumulation. No differences in pharmacokinetic parameters were noted between evaluations at week 6 or week 12. Changes in pharmacodynamic response of glucose, insulin, and C-peptide to chronic glyburide therapy were observed. Glyburide therapy significantly reduced plasma glucose levels at weeks 6 and 12 (percent changes in AUC0→4. glucose from baseline: week 0, −3 ± 11%; week 6, − 29 ± 13%; and week 12, −26 ± 19%). Pancreatic insulin secretion was acutely enhanced and maintained during long-term therapy. Responsiveness to therapy as assessed by the ratio of AUC0→4.glucose:AUC0→4.C-peptide was significantly improved at all weeks compared with baseline. No pharmacodynamic response differences were observed between the week 6 and the week 12 evaluations. CONCLUSIONS This study demonstrates that significant differences in glyburide pharmacokinetics and pharmacodynamics exist between single-dose and steady-state conditions. These differences support the need for careful dosage titration of glyburide to achieve a desired therapeutic response in patients with type II diabetes.