Soong T. Chiang

Introduction of a Composite Parameter to the Pharmacokinetics of Venlafaxine and its Active O-Desmethyl Metabolite

Venlafaxine is a structurally novel, nontricyclic compound that is being evaluated for the treatment of various depressive disorders. A randomized three‐period crossover study was conducted to obtain pharmacokinetic and dose proportionality data on the drug and its active metabolite, O‐desmethylvenlafaxine. Eighteen healthy young men received single doses of venlafaxine 25, 75, and 150 mg followed by 3 days of administration every 8 hours (q8h). Steady‐state elimination half‐life was 3 to 4 hours for venlafaxine and 10 hours for O‐desmethylvenlafaxine; both were independent of dose. Venlafaxine had a high oral‐dose clearance, ranging from 0.58 to 2.63 L/hr/kg across doses with the lowest mean clearance, 0.98 L/hr/kg, at the highest dose. The apparent clearance of O‐desmethylvenlafaxine was lower than venlafaxine, ranging from 0.21 to 0.66 L/hr/kg, and the lowest mean clearance, 0.33 L/hr/kg, occurred at the lowest dose. The area under the metabolite curve was two to three times greater than that for venlafaxine. Each compound had linear dose proportionality up to 75 mg q8h. A composite parameter incorporating venlafaxine plus O‐desmethylvenlafaxine was introduced (i.e., AUC [area under the curve] + activity factor · AUCm), which extended linearity to 150 mg q8h. In summary, venlafaxine is a high‐clearance drug that forms a metabolite with almost equal activity and demonstrates linear dose‐proportionality.

Effects of age and gender on venlafaxine and O-desmethylvenlafaxine pharmacokinetics.

This single‐ and multiple‐dose, nonrandomized, inpatient study was conducted to determine the effects of age and gender on the pharmacokinetic profiles of the antidepressant venlafaxine and its equally active metabolite, O‐desmethylvenlafaxine. The subjects were 18 elderly (age 60–80 yrs) and 18 young (age 21–44 yrs) subjects, 9 men and 9 women per age group. They received a single 50‐mg venlafaxine dose followed by 50‐mg doses every 8 hours for 5 days. No significant differences in venlafaxine single‐dose pharmacokinetics were seen between age groups, but the steady‐state half‐life increased 24% in the elderly. For O‐desmethylvenlafaxine, single doses had a significantly lower apparent clearance in the elderly (0.29 vs 0.38 L/hr/kg), longer half‐life (13.2 vs 10.3 hrs), and 14% greater steady‐state half‐life. For the composite (venlafaxine + O‐desmethylvenlafaxine), there was a nonsignificant 16% increase in elderly steady‐state area under the curve (AUC* = AUC + activity factor • AUCm), and AUC* was linear between doses and age groups. We conclude that venlafaxine dosage adjustments for age or gender are not necessary based on pharmacokinetics.

Metabolism and kinetics of oxaprozin in normal subjects

Absorption, biotransformation, excretion, and kinetics of Oxaprozin (4,5‐diphenyl‐2‐oxazolepropionic acid) were examined in subjects after an oral dose of 14C‐Oxaprozin alone as well as before, during, and after long‐term administration of unlabeled drug. A single dose of 14C‐oxaprozin was rapidly absorbed and the unchanged drug was essentially the only labeled substance in plasma. Recovery of radioactivity in excreta, mostly in urine, exceeded 90%. Major biotransformation routes were glucuronidatum of the carboxyl group and hydroxylation of the phenyl rings followed by glucuronidation. Administration of unlabeled Oxaprozin did not affect the absorption, qualitative, or quantitative metabolite profile, or recovery of l4C‐Oxaprozin. Following a single dose, the kinetic parameters for 14C and unchanged drug in plasma were nearly the same. A 2‐compartment model with first‐order elimination adequately describes kinetic disposition. The slow clearance (Clp), 0.08 to 0.12 l/hr, was almost entirely due to biotransformation and the plasma half‐lifes, which ranged from 49 to 69 hr, reflected the small Clp. The small volume of distribution (VDβ= 8 to 9 l) indicates limited extravascular distribution. Multiple doses of unlabeled drug, especially when given concurrently, increased the Clp of 14C‐oxaprozin. This effect is apparently related to decreased binding of high concentrations of Oxaprozin to plasma protein. As a result of increased Clp, steady‐state levels are only 40% of levels predicted from the single‐dose study.

Pharmacokinetics and Effect of Food on The Bioavailability of Orally Administered Venlafaxine

Venlafaxine is a unique antidepressant currently under evaluation for treatment of various affective disorders. The pharmacokinetics and relative bioavailability of venlafaxine were evaluated in healthy volunteers after oral administration. The bioavailability of 50 mg of venlafaxine as a tablet relative to a solution was determined in a two‐period randomized crossover study. The rate of absorption from the gastrointestinal tract was assessed by the time to peak plasma concentration (tmax), a model‐dependent calculation of the first‐order absorption rate constant, and a model‐independent calculation of mean residence time. The extent of absorption was assessed by peak plasma concentration (Cmax) and area under the concentration—time curve (AUC). No statistically significant differences were observed between the two formulations for either the rate or extent of absorption. Similarly, systemic concentrations of the active O‐demethylated metabolite did not significantly differ after administration of the two venlafaxine formulations. AUC ratios indicated that the relative bioavailabilities of the parent drug, and formulation of metabolite were approximately 98% and 92%, respectively, for the tablet versus the solution. A separate study was conducted to examine the influence of food on venlafaxine absorption from the 50‐mg tablet. A standard, medium‐fat breakfast eaten immediately before drug administration delayed the tmax of venlafaxine but did not affect Cmax or AUC. Therefore the tablet formulation of venlafaxine is bioequivalent to the oral solution, and the presence of food appears to decrease the rate but not the extent of absorption of venlafaxine from the tablet formulation. J Clin Pharmacol 1997;37:954–961.

Renal disease, age, and oxazepam kinetics

Effects of renal insufficiency and age on oxazepam kinetics were assessed in 13 normal subjects (21 to 72 yr old), four patients with renal insufficiency, and eight patients on hemodialysis. Normal intact oxazepam results were: mean elimination half‐life (t½), 10 hr; area under the curve (AUC), 6.0 μg·hr/ml; unbound oxazepam fraction (fup), 3.2%; maximum concentration of unbound oxazepam (Cmax, u), 16 ng/ml; and intrinsic (unbound drug) clearance (Clint), 2.9 llhrlkg. Less than 1% of the dose was excreted intact in urine. Age differences had no influence on results. In renal insufficiency patients, t½ was prolonged to 25 hr, fup increased to 7%, and Cmax, u and Clint were unchanged. Volume of distribution of unbound oxazepam (Vu) increased, thereby prolonging t½. In dialysis patients, t½ was prolonged to 33 hr, fup increased to 6.2%, and Cmax, u and Clint again were unchanged. Oxazepam was undialyzable; since unbound oxazepam disposition kinetics are not altered, no dosage adjustment for patients is necessary.

Oxaprozin disposition in renal disease

Effects of renal disease on the disposition kinetics of oxaprozin, a nonsteroidal antiinflammatory analgesic, were assessed in 15 subjects who were normal, renally impaired, or who had been undergoing hemodialysis. Oral dose clearance (Cloral), volume of distribution at steady‐state (Vssd), and elimination half‐life (tl/2) did not substantially differ among the three groups. Mean fraction unbound oxaprozin in plasma (fup) increased from 0.08% in the normal group to 0.18% and 0.28% in the two azotemic groups. Consequently, unbound drug kinetic parameters, including intrinsic clearance (Clint) and Vssdu of unbound drug were reduced from 2.9 l/hr/kg and 193 l/kg in normal subjects to approximately 1.6 l/hr/kg and 91 l/kg in azotemic patients. The smaller volume of distribution is consistent with a decrease in oxaprozin tissue binding in azotemia. The decreased plasma and tissue binding and lower Clint suggest that, in the treatment of azotemic patients with rheumatoid arthritis, the dose of oxaprozin should begin at 600 mg once a day.

Population Pharmacokinetics of Intravenous Amiodarone and Comparison with Two‐Stage Pharmacokinetic Analysis

The disposition of amiodarone, an antiarrhythmic agent was evaluated after a single intravenous infusion (5 mg/kg over 15 minutes) in patients of various ages and with various degrees of renal function and left ventricular function. The plasma concentration—time data were obtained from three clinical studies with similar protocols. The data were analyzed by nonlinear mixed‐effects modeling (NONMEM) to estimate the population pharmacokinetic parameters of amiodarone and to determine the significant demographic covariates affecting these parameters. The pharmacokinetic parameters of amiodarone (weight‐corrected) also were calculated using two‐stage analysis and were compared with the results obtained from the mixed‐effects analysis. The population plasma concentration—time profile of amiodarone was best described by a four‐compartment model. Demographic covariates (i.e., creatinine clearance and ejection fraction) did not improve the final pharmacostatistical model significantly. The results from the two‐stage analysis showed no significant relationship between amiodarone pharmacokinetic parameters and age, gender, renal function, or ejection fraction. The results from one study, however, demonstrated that advanced age (≥65 years) resulted in reduced amiodarone clearance coupled with a prolonged elimination half‐life. No such correlation was detected with NONMEM analysis, which may be partly attributable to the small number of elderly patients. Overall, the results from NONMEM analysis validated the results obtained from the two‐stage analysis.

Pharmacokinetic Interaction Between Multiple‐Dose Venlafaxine and Single‐Dose Lithium

Venlafaxine is a structurally novel antidepressant. Because lithium and antidepressants may be administered concomitantly, it is important to determine whether the disposition of venlafaxine and lithium is affected by coadministration. An open‐label study was conducted to evaluate the effects of multiple‐dose, steady‐state venlafaxine administration on the pharmacokinetics of a single oral dose of lithium. Analogously, the effects of administration of a single‐dose of lithium on the disposition of venlafaxine and its active metabolite, O‐desmethylvenlafaxine, after multiple‐dose administration of venlafaxine were assessed. Administration of 600 mg lithium carbonate did not affect venlafaxine absorption. Lithium significantly reduced the renal clearance of venlafaxine from 0.053 to 0.027 L/h/kg. However, renal excretion is not a major elimination pathway for venlafaxine; thus, lithium did not affect the total clearance of venlafaxine. Lithium administration had similar effects on elimination of O‐desmethylvenlafaxine. Multiple‐dose administration of 50 mg of venlafaxine every 8 hours produced a slight increase in the rate of lithium absorption, but did not affect the extent of lithium absorption. Total clearance (0.026 L/h/kg) and steady‐state volume of distribution (0.71 L/kg) of lithium were not affected by administration of venlafaxine. Thus, there were no clinically significant pharmacokinetic interactions between venlafaxine and lithium.

Bioavailability of once-daily venlafaxine extended release compared with the immediate-release formulation in healthy adult volunteers

Abstract Two open-label, randomized, crossover studies, one single- and one multiple-dose, were conducted to assess the relative bioavailability of two formulations of once-daily venlafaxine extended release (XR) 75 and 150 mg compared with the immediate-release (IR) formulation of venlafaxine. Healthy adults (12 men, 12 women) aged 18 to 45 years were enrolled in each study. Frequent blood samples were taken for determination of the plasma concentrations of venlafaxine and its active metabolite, O-desmethylvenlafaxine (ODV). In the single-dose study, the 2 × 75-mg XR formulation and the 150-mg XR formulation were bioequivalent with respect to the rate and extent of absorption of venlafaxine and the formation of ODV, and the area under the plasma concentration—time curve (AUC) of both XR formulations and the AUC of the IR formulation also were bio-equivalent after normalization for dose. In the multiple-dose study, the three XR formulations were also bioequivalent with respect to the rate and extent of absorption of venlafaxine and formation of ODV, and the AUC of all three XR formulations compared with the AUC of the IR formulation also showed bioequivalence. Overall, the once-daily venlafaxine XR formulations provided the same total exposure (measured by AUC) to both venlafaxine and ODV. Thus it can be predicted that patients will obtain the same response with the XR formulations as with the IR formulations.

PHARMACOKINETICS OF ONCE-DAILY VENLAFAXINE EXTENDED RELEASE IN HEALTHY VOLUNTEERS

Abstract Three pharmacokinetic studies were performed to assess the effects of food intake and morning versus evening administration of once-daily venlafaxine extended release (XR) on the pharmacokinetic disposition of venlafaxine and its active metabolite O-desmethylvenlafaxine (ODV). Forty-six healthy adults (43 men and 3 women), 18 to 45 years of age with body weight within 15% of normal for height and frame, were enrolled in these studies. In two studies, venlafaxine XR 75-mg or 150-mg capsules were administered to healthy subjects in fasting state or after a high-fat breakfast. In a third study, once-daily venlafaxine XR 75 mg was administered for 4 days (to steady state) either in the morning or in the evening. All three studies were conducted with a two-period crossover study design, and the plasma samples were assayed using high-performance liquid chromatography for the concentrations of venlafaxine and ODV. The steady-state pharmacokinetic profile of venlafaxine XR was not affected by the time of administration (morning or evening), and the single-dose pharmacokinetic profile was not affected by the presence or absence of food. Therefore, the venlafaxine XR formulation exhibits a controlled rate of release, and administration of venlafaxine XR with a high-fat meal does not produce a dose-dumping effect. Based on the results of these studies in healthy volunteers, once-daily venlafaxine XR 75 or 150 mg may be given without regard to meals and once-daily venlafaxine XR 75 mg may be taken either in the morning or evening without affecting the pharmacokinetic disposition of or systemic exposure to venlafaxine and ODV.