Howard Uderman

A Dose‐Escalation Study of the Safety, Tolerability, and Pharmacokinetics of Intravenous Gatifloxacin in Healthy Adult Men

Study Objectives. To examine single‐ and multiple‐dose safety, tolerability and pharmacokinetics of gatifloxacin administered as daily 1‐hour intravenous infusions for 14 days, and to determine the effect of gatifloxacin on glucose tolerance, pancreatic β‐cell function, and electrocardiogram (ECG).

Pharmacokinetics and tolerability of buspirone during oral administration to children and adolescents with anxiety disorder and normal healthy adults.

A 21‐day, open‐label, multisite, dose escalation study comprising three demographic groups (children, adolescents, and adults) was performed to determine the pharmacokinetics and tolerability of orally administered buspirone. Thirteen children and 12 adolescents with anxiety disorder and 14 normal healthy adults were escalated from 5 to 30 mg buspirone bid over the 3‐week study. Pharmacokinetic analysis revealed that buspirone was rapidly absorbed in all study groups, reaching peak levels at about 1 hour after administration. Peak plasma buspirone concentrations (Cmax) were highest in children and lowest in adults at all three dose levels (7.5, 15, 30 mg bid). However, 1‐pyrimidinylpiperazine (1‐PP), the primary metabolite of buspirone, exhibited a different plasma concentration‐time profile; Cmax was significantly higher in children than in either adolescents or adults at all concentrations. In addition, TAUC0‐T for 1‐PP was significantly higher in the children cohort relative to adolescents and adults. Buspirone was generally safe and well tolerated at doses up to 30mgbid in adolescents and adults and most of the children. The most frequently reported adverse events in children and adolescents were lightheadedness (68%), headache (48%), and dyspepsia (20%); 2 children withdrew from the study at the higher doses (15 mg and 30 mg bid) due to adverse effects. In adults, the most common adverse effect was somnolence (21.4%); lightheadedness, nausea, vomiting, and diarrhea were also reported, although these were mild in intensity.

Effects of Standard and Supratherapeutic Doses of Nelfinavir on Cardiac Repolarization: A Thorough QT Study

This was a randomized, 4‐way crossover, third‐party‐blinded study in 68 healthy subjects to assess the effect of nelfinavir on QTc interval. Treatments included (A) nelfinavir 1250 mg every 12 hours on days 1–4, (B) nelfinavir 1250 mg every 12 hours on days 1–3 plus 3125 mg on day 4, (C) placebo, and (D) moxifloxacin 400 mg every 24 hours on days 1–4. Pharmacokinetics and triplicate 12‐lead electrocardiograms were performed over 12 hours on days 1 and 4. Time‐matched, placebo‐subtracted, baseline‐adjusted changes in QT intervals with Fridericias (QTcF) correction were determined following nelfinavir and moxifloxacin administration. Neither dose of nelfinavir had a clinically relevant effect on the QTcF interval on day 4 (primary endpoint) and day 1 because at every time point the upper 90% confidence limit was below 10 milliseconds and, furthermore, the mean difference was below 5 milliseconds. Additionally, there was no clinically relevant effect on QTcB (Bazetts correction), uncorrected QT, or the RR interval on days 1 or 4. Pharmacokinetics confirmed adequate systemic exposure to nelfinavir and moxifloxacin. While nelfinavir exposure was higher in poor compared with extensive metabolizers of CYP2C19 isozyme, there were no corresponding significant differences in QTcF change from placebo. At clinically relevant, doses nelfinavir is unlikely to cause QTc prolongation.

Open‐Label, Nonrandomized Study of the Effects of Gatifloxacin on the Pharmacokinetics of Midazolam in Healthy Male Volunteers

Study Objective. To confirm findings from an in vitro study that showed gatifloxacin did not substantially inhibit cytochrome P450 (CYP) 3A4 model substrate metabolism.

Pharmacodynamic Effects of Multiple Doses of Omapatrilat in Healthy Subjects

Clinical Pharmacology & Therapeutics (1999) 65, 132–132; doi:

Influence of CYP2C19 polymorphism on the pharmacokinetics of nelfinavir and its active metabolite.

AIMS This study reports the pharmacokinetics of nelfinavir, its active metabolite, M8, and active moiety (nelfinavir + M8) in volunteers genotyped for CYP2C19 as extensive metabolizer (*1*1; n = 38), heterozygous poor metabolizer (PM) (*1*2; n = 22) and homozygous PM (*2*2; n = 6). METHODS Subjects received nelfinavir at normal dose (3.5 days of 1250 mg q12h) or high dose (1250 mg q12h for 3 days and single dose of 3125 mg on day 4). Steady-state plasma samples were analysed by high-performance liquid chromatography/ultraviolet assay to determine pharmacokinetics. RESULTS At steady state, the mean C(max) was 42% [95% confidence interval (CI) 19, 69] and 63% (95% CI 20, 122) higher, and mean AUC was 51% (95% CI 24, 83) and 85% (95% CI 32, 159) higher for *1*2 and *2*2 compared with *1*1 subjects, respectively. For M8, the mean C(max) and AUC were 35% (95% CI 6, 55) and 33% (95% CI -3, 56), respectively, lower for *1*2 compared with *1*1 subjects. M8 was not detectable in *2*2 subjects. The mean C(max) and AUC values for the active moiety were higher by 30-35% for the *1*2 and *2*2 compared with *1*1 subjects. CONCLUSIONS Mutation in CYP2C19 increased the systemic exposure of nelfinavir and reduced the exposure of M8. No significant differences were noted among the heterozygous (*1*2) and homozygous (*2*2) PMs. These changes are not considered to be clinically relevant and hence the use of nelfinavir does not require prior assessment of CYP2C19 genotype.

Interaction of nefazodone (N) and fluoxetine (F)

Clinical Pharmacology & Therapeutics (1996) 59, 180–180; doi: 10.1038/sj.clpt.1996.218

Steady-State PK of Omapatrilat in Healthy Subjects

Clinical Pharmacology & Therapeutics (1999) 65, 133–133; doi:

Effects of Food on the Pharmacokinetics of Irbesartan/Hydrochlorothiazide Combination Tablet

AbstractObjective: The effects of food on the pharmacokinetics of an irbesartan/ hydrochlorothiazide combination tablet were assessed in 16 healthy young male volunteers. Methods: Each subject received a 150mg/12.5mg irbesartan/hydrochlorothiazide tablet following an overnight (approximately 10 hours) fast or 5 minutes after a high fat breakfast according to a randomisation schedule. Two treatments were separated by at least a 7-day washout period. Serial blood samples were collected over a 72-hour period and plasma samples were analysed for irbesartan and hydrochlorothiazide using validated procedures. Results: No statistically significant effects of food were observed in any of the irbesartan pharmacokinetic parameters analysed, except for the time to peak observed concentration (tmax), which was prolonged from a median of 1.0 hour in the fasted state to 2.0 hours in the fed state. The geometric means for irbesartan eak concentrations (Cmax) and area under the plasma concentration-time curve extrapolated to infinity (AUC0-∞) decreased less than 4% under the fed condition compared with the fasted state. The geometric means for hydrochlorothiazide decreased 21 and 8% for Cmax and AUC0-∞, respectively, when the combination tablet was administered with food compared with the fasted state. The decrease in Cmax was statistically significant. Food also significantly prolonged the median tmax, 1.5 hours vs 3.5 hours. However, these changes in the pharmacokinetic parameters were not clinically significant. Conclusion: The combination tablet of irbesartan/hydrochlorothiazide can be administered without regard to meals.

Fosinopril and Hydrochlorothiazide Combination versus Individual Components: Lack of a Pharmacokinetic Interaction

OBJECTIVE: To evaluate the pharmacokinetic interaction and bioequivalence of a combination formulation of the angiotensin-converting enzyme inhibitor fosinopril and the diuretic hydrochlorothiazide (HCTZ). METHODS: In an open-label, balanced, randomized incomplete block, three-way crossover fashion, healthy men received single doses of three of four regimens in one of two independent studies. Regimens for study A (36 subjects): (1) fosinopril 10-mg tablet, (2) HCTZ 12.5-mg tablet, (3) a combination tablet of fosinopril 10 mg plus HCTZ 12.5 mg, or (4) coadministered tablets of fosinopril 10 mg and HCTZ 12.5 mg. Study B (40 subjects) received: (1) fosinopril 20-mg tablet, (2) HCTZ 12.5-mg tablet, (3) a combination tablet of fosinopril 20 mg plus HCTZ 12.5 mg, or (4) coadministered tablets of fosinopril 20 mg and HCTZ 12.5 mg. RESULTS: There was no evidence of any significant effect of HCTZ on the pharmacokinetics of fosinoprilat, based on maximum concentration value, AUC, or cumulative urinary recovery over 24 hours. Fosinoprilat had no clinically important effect on the pharmacokinetics of HCTZ only slightly decreasing its AUC by 14% in study A. Coadministration was well tolerated; no new adverse events were reported with the combination tablet. CONCLUSIONS: Fosinopril and HCTZ in a combination tablet display pharmacokinetic profiles similar to those achieved when either drug is administered alone or when coadministered in separate tablets. When used with HCTZ, the favorable pharmacokinetic feature of fosinopril, dual and compensatory pathways of renal and hepatic elimination, is preserved.