Benito J. Cerimele

Pharmacokinetics and Safety of Duloxetine, a Dual‐Serotonin and Norepinephrine Reuptake Inhibitor

The pharmacokinetics and safety of duloxetine were evaluated in a single‐blind, placebo‐controlled, escalating multiple‐dose study in 12 healthy male subjects. In the treatment group (n = 8), duloxetine was administered orally at a starting dose of 20 mg twice daily (bid) and escalated at weekly intervals to 30 mg bid, then to 40 mg bid. The observed plasma concentration‐time data at all three dose levels were adequately described by a one‐compartment model with a first‐order absorption rate constant. The mean oral clearance, apparent volume of distribution, and half‐life values were 114 L/h (range: 44 to 218 L/h), 1943 L (range: 803 to 3531 L), and 12.5 h (range: 9.2 to 19.1 h), respectively. Somnolence, nausea, and dry mouth were observed following the initial dose, but they resolved with continuing drug administration. Duloxetine was not associated with clinically significant changes in blood pressure (BP) or heart rate (HR) measured in the standing position. However, in recumbent position, small increases in systolic (≤ 9 mmHg) and diastolic (≤ 5 mmHg) BP and small decreases in HR (≤ 6 beats/min) were observed. Abrupt discontinuation of duloxetine was associated with a small increase in mean HR (≤ 12beats/min). In 3 subjects, abrupt discontinuation was also associated with transient sleep disturbance. No clinically important changes in electrocardiograms, cardiac intervals, clinical laboratory tests, and neurological functions were observed. These results indicate that duloxetine exhibits linear pharmacokinetics with respect to dose and duration of treatment and that a multiple oral dose regimen starting at 20 mg bid and gradually escalating up to 40 mg bid was generally well tolerated.

Injection Site Effects on the Pharmacokinetics and Glucodynamics of Insulin Lispro and Regular Insulin

OBJECTIVE The pharmacokinetics and glucodynamics of a new insulin analog, insulin lispro, and regular human insulin were compared and contrasted after subcutaneous administrations in femoral, deltoid, and abdominal injection sites. RESEARCH DESIGN AND METHODS Single 0.2 U/kg doses of insulin lispro and regular insulin were administered to 12 healthy subjects in a six-way randomized crossover fashion. Each dose was given after an overnight fast in one of three injection sites: abdominal, deltoid, or femoral. Study drugs were given during a manual euglycemic glucose clamp. Blood samples were collected over the 12-h clamp for measurement of insulin-reactive components, with pharmacokinetic and glucodynamic measurements derived from these serum insulin and clamp measurements. RESULTS Glucodynamic comparisons between insulin lispro and regular insulin showed a greater maximum infusion rate (Rmax) at an earlier time (TRmax), regardless of injection site. The total glucose infused (Gtot) showed nearly identical values between sites for insulin lispro. Regular insulin showed greater Gtot values from deltoid and femoral injections. When comparisons were made between drugs, regular insulin produced significantly greater Gtot, primarily driven by the increased Gtot from deltoid and femoral injections. Greater maximum serum insulin concentrations (Cmax) were experienced with insulin lispro at earlier times (tmax), regardless of the injection site (P < 0.001). Abdominal administrations produced the greatest Cmax values at the earliest tmax for both regular insulin and insulin lispro. Deltoid and femoral injections had lower Cmax values for both compounds. Shifts also occurred with tmax, although these shifts were much greater with regular insulin than with insulin lispro. Equivalent area under the curve (AUC) values were found when compared between compounds. CONCLUSIONS Slower absorption from deltoid and femoral administrations resulted in an increased duration of action for both regular insulin and insulin lispro when compared to abdominal administration. However, notable increases in the onset of action were only apparent with regular insulin. The consistency with insulin lispro response from abdominal and extremity injection sites allows more potential sites for subcutaneous injection with an assured rapid response.

The effect of sertraline on the pharmacokinetics of desipramine and imipramine

To examine the pharmacokinetic interaction between the selective serotonin reuptake inhibitor sertraline and the tricyclic antidepressants desipramine or imipramine in 12 healthy male subjects.

Assessment of the potential for a pharmacokinetic interaction between fluoxetine and terfenadine

To assess whether fluoxetine and its metabolite, norfluoxetine, are inhibitors of the metabolism of CYP3A substrates.

Effect of Dirithromycin on Human CYP3A In Vitro and on Pharmacokinetics and Pharmacodynamics of Terfenadine In Vivo

Terfenadine is metabolized by the cytochrome P‐450 3A subfamily of enzymes (CYP3A). Certain macrolide antibiotic agents inhibit CYP3A and, when coadministered with terfenadine, result in a drug interaction. The authors compared the abilities of dirithromycin (a new macrolide antibiotic agent), its major metabolite erythromycylamine, and the known CYP3A substrate terfenadine to inhibit CYP3A in vitro. The hydroxylation of midazolam in human liver microsomes was used as a probe for CYP3A activity. Dirithromycin and erythromycylamine were low affinity inhibitors of CYP3A (inhibitory binding affinities of 493 μmol/L and 701 μmol/L, respectively); conversely, terfenadine was a moderate affinity inhibitor (inhibitory binding affinity of 28 μmol/L). Based on these data, the authors tested the hypothesis that dirithromycin would not interact with terfenadine in humans. Six healthy men received terfenadine alone (60 mg twice daily) for 8 days, after which dirithromycin (500 mg once daily) was added to the terfenadine regimen for an additional 10 days. The pharmacokinetics of terfenadine (and its acid metabolite) and the QTc interval were measured during both treatments, and it was found that neither parameter was affected. In this study, dirithromycin was found to have low affinity for human CYP3A in vitro, which is in accordance with the studys finding that in vivo dirithromycin has no major effect on the metabolism of the CYP3A substrate terfenadine in humans.

Tmax: an unconfounded metric for rate of absorption in single dose bioequivalence studies.

AbstractPurpose. While peak drug concentration (Cmax) is recognized to be contaminated by the extent of absorption, it has long served as the indicator of change in absorption rate in bioequivalence studies. This concentration measure per se is a measure of extreme drug exposure, not absorption rate. This paper redirects attention to Tmax as the absorption rate variable. Methods. We show that the time to peak measure (Tmax), if obtained from equally spaced sampling times during the suspected absorption phase, defines a count process which encapsulates the rate of absorption. Furthermore such count data appear to follow the single parameter Poisson distribution which characterizes the rate of many a discrete process, and which therefore supplies the proper theoretical basis to compare two or more formulations for differences in the rate of absorption. This paper urges limiting the use of peak height measures based on Cmax to evaluate only for dose-dumping, a legitimate safety concern with, any formulation. These principles and techniques are illustrated by a bioequivalence study in which two test suspensions are compared to a reference formulation. Results. Appropriate statistical evaluation of absorption rate via Tmax supports bioequivalence, whereas the customary analysis with Cmax leads to rejection of bioequivalence. This suggests that the inappropriate use of Cmax as a surrogate metric for absorption rate contributes to the unpredictable and uncertain outcome in bioequivalence evaluation today.

Comparative pharmacokinetics and glucodynamics of two human insulin mixtures. 70/30 and 50/50 insulin mixtures.

OBJECTIVE To compare and contrast the pharmacokinetics and glucodynamics of two insulin mixtures, one of 50% NPH human insulin and 50% Regular human insulin (50/50) and one of 70% NPH human insulin and 30% Regular human insulin (70/30), in healthy male volunteers after subcutaneous administrations of 0.3 U/kg. RESEARCH DESIGN AND METHODS We administered single doses of 50/50 and 70/30 insulins to 18 volunteers in a randomized crossover fashion. All subjects received 0.3 U/kg of each mixture separated by at least 7 days. Each dose was given after an overnight fast and during a glucose clamp to maintain a euglycemic state. We measured serum insulin and Cpeptide concentrations through frequent blood sampling after each treatment. Pharmacokinetic measurements were calculated from insulin data corrected for C-peptide, including maximum insulin concentration (Cmax), time to maximum insulin concentration (tmax), terminal rate constant (β), area under the curve from 0 to ∞, (AUC x0), and mean residence time (MRT). Pharmacodynamic measurements were summarized from C-peptide concentrations (minimum C-peptide concentration [Cmin], time to minimum C-peptide concentration [tmin], area between the C-peptide baseline and the C-peptide suppression curve [AOCc], absolute maximal difference from baseline [Sdiff] and glucose clamp measurements. The glucose clamp measurements included maximum infusion rates (Rmax) and time to Rmax (TRmax) from glucose infusion rate (GIR) documentation, as well as cumulative glucose infused during the first 4 h (40Gtot) and total glucose infused (Gtot) during the study. RESULTS For the pharmacokinetic assessment, statistically greater values of insulin Cmax and β were found for the 50/50 mixture, whereas the 70/30 mixture had a greater MRT. Statistical differences were also detected in glucodynamics, with greater values of Rmax and (40Gtot) found with the 50/50 mixture. Notably, differences were not detected for insulin AUCx0 and Gtot values. CONCLUSIONS Higher insulin concentrations and a greater initial response were present with the 50/50 mixture, but the two mixtures had equivalent bioavailability and cumulative effects. These results support use of the 50/50 mixture in situations where greater initial glucose control is required.

Effect of Zatosetron on Ipecac‐Induced Emesis in Dogs and Healthy Men

Serotonin receptor (5‐HT3) antagonists provide effective antiemetic therapy in cancer patients receiving emetogenic chemotherapy, such as cisplatin. Animal studies have shown that 5‐HT3 receptor antagonists also have antiemetic activity in ipecac‐induced emesis. The authors investigated the antiemetic activity of zatosetron maleate, a 5‐HT3 receptor antagonist, on ipecac‐induced emesis in dogs and healthy men. They also evaluated the effect of ipecac administration on serotonin release and metabolism by measuring urinary 5‐hydroxyindoleacetic acid (5‐HIAA) excretion in healthy men. In separate randomized, placebo‐controlled trials, 20 dogs received zatosetron intravenously and eight healthy men received zatosetron (50 mg) orally, followed by ipecac syrup. In both trials, emetic response to ipecac was recorded, including the number and time of vomits and retches. Zatosetron treatment inhibited and delayed ipecac‐induced emesis in both groups. In dogs, zatosetron inhibited ipecac‐induced emesis in a dose‐dependent manner with a 100‐μg/kg dose producing complete inhibition. In men, zatosetron administration resulted in fewer emetic episodes after ipecac than had occurred with placebo administration (P = .03); vomiting was completely inhibited by zatosetron. In men, ipecac administration did not affect the urinary 5‐HIAA/creatinine ratio (mg/g) or 5‐HIAA excretion rate (μg/hour). Our study demonstrates that zatosetron has similar efficacy on ipecac‐induced emesis in healthy men, as has been shown previously with other 5‐HT3 receptor antagonists in chemotherapy‐induced emesis in cancer patients. We did not observe the increase of urinary 5‐HIAA in our study with ipecac‐induced emesis, however, as has been described previously in cisplatin‐induced emesis. Our study indicates that ipecac‐induced emesis may be a useful model for testing 5‐HT3 receptor antagonists for antiemetic activity in dogs and healthy men.

Symmetrical Crossover Designs for Bilateral Pharmacokinetic Drug Interactions

Bilateral pharmacokinetic interaction studies are performed to test if the coadministration of the two drugs alters the kinetics of either one. For this purpose, standard designs are crossovers in which the two drugs are successively given alone and together. Because the systemic concentration of one drug, A, will be zero when the other drug, B, is given alone and vice versa, two separate analyses for Drugs A and B are required. Two symmetrical designs which generate identical analyses for Drugs A and B are reviewed: the dual balanced two-period and the balanced Latin Square three-period designs. Their efficiency in accurately and precisely estimating direct treatment differences (AB-B) or (AB-A) is compared, when analyzed with a standard linear mixed model that either does or does not include a first-order carry-over effect. From this evaluation, the balanced three-period design is preferred because of its 25% superior efficiency when no carryover effect is present. In the presence of carry-over, the three-period design also produces unbiased estimators for the direct treatment and carry-over effects whose variances are proportional to the within-subject variability.

Local and Systemic Phentolamine Antagonism of Norepinephrine‐Induced Hand Vein Constriction

The dorsal hand vein distention technique has been used to study the effects of α‐adrenergic receptor antagonists on α‐agonist‐induced venoconstriction. Using this technique, we investigated the dose‐effect relationships between different intravenous routes of phentolamine (an α‐antagonist) administration on norepinephrine (an α‐agonist)‐induced hand vein constriction. Hand vein studies were done on healthy men; each man was studied on up to four occasions. On one occasion for each man, graded doses of phentolamine were infused into a hand vein preconstricted (submaximally) with norepinephrine. The dose of phentolamine producing a half maximal response (ED50) for reversal of venoconstriction, and the maximal reversal were calculated. On the other three occasions (randomly allocated) for each man, graded doses of norepinephrine were infused into a hand vein before and during intravenous infusions of (1) control (vehicle solutions); (2) systemic (other arm vein) phentolamine; and (3) local (hand vein) phentolamine. Systemic and local phentolamine dose ratios (ED50 of norepinephrine during phentolamine, divided by ED50 of norepinephrine before phentolamine; divided by the control dose ratio) were calculated. These studies show that phentolamine (administered directly into a preconstricted hand vein) can completely reverse norepinephrine‐induced venoconstriction. Phentolamine, administered by either local or systemic intravenous infusion, induces a significant right‐ward shift (approximately 10‐fold) in responsiveness to norepinephrine‐induced venoconstriction. To achieve comparable degrees of α‐antagonism, however, systemic phentolamine must be administered intravenously at a dose approximately 3,000‐fold higher than that of local phentolamine. Implications of these dose‐effect relationships, and their possible application to the treatment of norepinephrine extravasation and to hand vein studies with other receptor agonist‐antagonist combinations, are discussed.