John Lettieri

Itraconazole alters the pharmacokinetics of atorvastatin to a greater extent than either cerivastatin or pravastatin

3‐Hydroxy‐3‐methylglutaryl coenzyme A reductase inhibitors (statins) are metabolized by distinct pathways that may alter the extent of drug‐drug interactions. Cerivastatin is metabolized by cytochrome P450 (CYP)3A4 and CYP2C8. Atorvastatin is metabolized solely by CYP3A4, and pravastatin metabolism is not well defined. Coadministration of higher doses of these statins with CYP3A4 inhibitors has the potential for eliciting adverse drug‐drug interactions.

Pharmacokinetics, Pharmacodynamics, and Safety of Metrifonate in Patients with Alzheimer's Disease

Metrifonate is converted nonenzymatically to 2,2, dimethyl dichlorovinyl phosphate (DDVP), an inhibitor of acetylcholinesterase (AChE). This 21‐day, randomized, double‐blind, placebo‐controlled trial of metrifonate in patients with Alzheimers disease (n = 27) evaluated four doses, each administered orally once daily. All patients received a loading dose (LD) for 6 days followed by a maintenance dose (MD) for 15 days. The treatment groups were: panel 1, LD = 1.5 mg/kg (75–135 mg), MD = 0.25 mg/kg (12.5–25 mg); panel 2, LD = 2.5 mg/kg (125–225 mg), MD = 0.40 mg/kg (20–35 mg); panel 3, LD = 4.0 mg/kg (200–335 mg), MD = 0.65 mg/kg (30–60 mg); and panel 4, LD = 4.0 mg/kg (200–335 mg), MD = 1.0 mg/kg (50–90 mg). All metrifonate doses were well tolerated. Most adverse events were mild to moderate in intensity, gastrointestinal in nature, and transient. Mean area under the concentration—time curve (AUC) and maximum concentration (Cmax for both metrifonate and DDVP increased in relation to dose. Metrifonate and DDVP had similar, largely dose‐independent mean values for time to Cmax (tmax) and half‐life (t1/2). There was little or no accumulation of either metrifonate or DDVP with long‐term administration. After 21 days of treatment, mean percent erythrocyte AChE inhibition was 14%, 35%, 66%, 77%, and 82% for placebo and panels 1 through 4, respectively. Cognitive improvement was observed with the two highest metrifonate doses. These results reflect favorable safety and pharmacokinetic profiles for the use of metrifonate in the treatment of Alzheimers disease.

Absolute bioavailability of moxifloxacin

Moxifloxacin (BAY 12-8039) is an investigational 8-methoxy-fluoroquinolone with broad-spectrum gram-positive and gram-negative activity. To determine the absolute bioavailability of moxifloxacin, this open-label, randomized, crossover study compared the pharmacokinetic characteristics of a single 100-mg dose administered either orally or intravenously as a 60-minute infusion in 10 healthy male volunteers (mean age [+/- SD], 29.3+/-7.1 years; mean weight [+/- SD], 77.7+/-8.7 kg). Geometric mean values for oral/IV moxifloxacin were as follows: peak serum concentration, 1.15/1.34 mg/L, and area under the concentration-time curve over 48 hours, 9.86/10.89 mg x h/L. The geometric mean absolute bioavailability of oral moxifloxacin was 91.8%. Mean renal clearance was approximately 2.3 L/h after administration of both the single oral and IV formulations, which suggests lack of active tubular secretion of moxifloxacin. Both the oral and IV formulations were well tolerated, with 5 reported possible or probable drug-related adverse events; they included headache, nausea, and localized urticaria. In summary, a single oral dose of moxifloxacin was extensively absorbed in healthy young men. Further studies are necessary in actual patients to confirm the viability of IV to oral conversion at the same dose of moxifloxacin.

Effect of Food on the Pharmacokinetics of a Single Oral Dose of Moxifloxacin 400mg in Healthy Male Volunteers

ObjectiveTo investigate the effects of concomitant food intake on the pharmacokinetics of a single oral dose of moxifloxacin 400mg.DesignThis was a randomised 2-way nonblinded crossover study in healthy volunteers.Participants18 young, healthy, male volunteers were enrolled in the study, of whom 16 were considered evaluable for the pharmacokinetic analysis.MethodsMoxifloxacin was given under 2 conditions separated by a 1-week washout period: fasted and fed (immediately after a standardised high fat breakfast). Concentrations of moxifloxacin in serum were determined by a validated high performance liquid chromatography procedure with fluorescence detection.Outcome measuresPharmacokinetic parameters such as maximum concentration (Cmax), time to reach Cmax (tmax), area under the concentration-time curve from zero to 48 hours (AUC48h), AUC from zero extrapolated to infinity (AUC∞) and elimination half-life (t1/2,z) were estimated using noncompartmental methods. The natural logarithms of AUC and Cmax were analysed using analysis of variance. Bioequivalence of the 2 treatments was determined at the 5% significance level with the two 1-sided tests procedure and limits of 80% and 125% for AUC and 70 to 143% for Cmax.ResultsThe mean serum concentration versus time profiles were similar between the 2 treatments. The geometric mean AUC∞ values under fed and fasted conditions were almost identical, 37.7 versus 38.5 mg/L · h, respectively [90% confidence interval (CI) of the ratio of fed versus fasted based on geometric least-square means was 0.95, 1.00]. Geometric mean Cmax values were slightly reduced by food, 2.5 versus 2.8 mg/L, respectively (90% CI of fed versus fasted based on geometric least-square means was 0.78, 0.98). The absorption of moxifloxacin seems to be mildly delayed because of the effect of food; the median tmax values were 1.0 and 2.5 hours for fasted and fed conditions, respectively. The single oral dose of moxifloxacin 400mg was well tolerated when taken with and without food.ConclusionsThe criteria for bioequivalence with respect to Cmax and AUC∞ were met when moxifloxacin 400mg was given on an empty stomach or immediately after a high fat meal. Moxifloxacin may be given to patients with or without food.

The influence of age and gender on the pharmacokinetics of moxifloxacin.

ObjectiveMoxifloxacin is a new 8-methoxyfluoroquinolone with a broad antibacterial spectrum. The purpose of the present study was to determine the effects of age and gender on pharmacokinetics, surrogate pharmacodynamics, safety and tolerability of a single dose of moxifloxacin.DesignThis was a randomised, double-blind, placebo-controlled, parallel-group single dose trial in young and elderly healthy volunteers.Patients and participantsThe study included 36 volunteers in 3 age and gender groups: young males (mean age 32 years), elderly males (mean age 74 years), and elderly females (mean age 74 years).MethodsParticipants received either a single 200mg oral dose of moxifloxacin (8/group) or placebo (4/group). Blood samples for moxifloxacin pharmacokinetics were obtained before and up to 48 hours after administration. Urine samples were collected for pharmacokinetics, and volunteers were monitored for clinical adverse events and laboratory abnormalities.ResultsMaximum plasma concentration (Cmax) and area under the plasma concentration-time curve (AUC) were higher in elderly females than in elderly males; however, when normalised for bodyweight, these pharmacokinetic parameters were not significantly different between the groups. Moreover, the plasma pharmacokinetics in elderly males were not meaningfully different from those in young males. Elimination half-life averaged 12 to 13 hours for the 3 groups. Surrogate pharmacodynamic measures were derived using AUC/MIC (minimal inhibitory concentration) and Cmax/MIC ratios. These assessments indicated that, given the linear pharmacokinetics of moxifloxacin previously demonstrated, a dose of 400mg would produce mean Cmax/MIC values in the different subgroups ranging from 10.4 to 15.4 for an MIC of 0.25, and 20.8 to 30.8 for an MIC of 0.125. The corresponding ranges of projected AUC/MIC ratios would be 112 to 158 for an MIC of 0.25, and 224 to 314 for an MIC of 0.125. The accepted target values of AUC/MIC and Cmax/MIC for quinolones are 125 and 10, respectively. There were no serious adverse events or differences in adverse event profiles between the groups.ConclusionsMoxifloxacin does not exhibit age- or gender-dependent pharmacokinetics. Oral doses of 200 to 400mg yield effective antibacterial concentrations on the first day of administration.

Disposition and Pharmacokinetics of 14C-Nitrendipine in Healthy Volunteers

Six healthy male volunteers were each given a single 20 mg dose of 14C-labeled nitrendipine as an oral suspension. Urine, feces, and plasma were collected after dosing and assayed for total radioactivity. Urine and plasma were also assayed by capillary gas chromatography for nitrendipine and five metabolites. A mean of 77 ± 7.3% of the dose was excreted in the urine over 96 h, 70% was excreted within 24 h, and 76% within 48 h of dosing. The 48 h cumulative urinary excretion of nitrendipine metabolites accounted for 42 ± 4%, of the dose. Thus, ∼ 55% of the radioactivity excreted in the urine was present in the form of measured metabolites. Fecal recovery of radioactivity accounted for 8.1 ± 4.0% of the dose. Total recovery of radioactivity in urine and feces collected over 96 h was 85.1 ± 8.1% of the dose. When mean plasma levels of unchanged nitrendipine and five metabolites were compared with the concentration of total radioactivity in plasma, nitrendipine accounted for 2.4%, and the five metaolites for 80% of the total radioactivity in plasma detected 0–12 h after dose. The highest concentrations of nitrendipine, metabolites, and total radioactivity were attained between 0.5 and 1.5 h after dosing. The results show that on the average at least 77% of the dose was absorbed after oral administration, and only 8% of the dose was excreted in the feces. Most of the radioactivity in plasma and urine was attributed to nitrendipine and five metabolites.

Bioequivalence of Different Nitrendipine Tablet Dosage Formulations

A five-way crossover study with 30 prescreened volunteers was performed to compare two dosage formulations of Miles nitrendipine tablets with corresponding Bayer A G tablet formulations. All tablet formulations were also compared with a 20 mg liquid suspension dose of nitrendipine to determine the relative bioavailability of the tablet formulations. The nitrendipine and nitrendipine metabolite data obtained from the 26 volunteers who completed the study were examined using the General Linear Models of the Statistical Analysis System statistical package. The four tablet formulations were found to be bioequivalent in the extent of their absorption, as judged by area under the curve (AUC) values calculated using either the unchanged drug or the metabolite concentrations in plasma. The AUC values were in strong agreement with the AUC values reported for other nitrendipine tablet formulations in another bioequivalence study. In both studies 20 mg was given, and the relative bioavailability of tablet formulations was ∼ 70% when compared with a 20 mg liquid suspension dose. No significant differences were observed between either one of the Miles tablets and the Bayer tablet of the same strength, with regard to maximum nitrendipine plasma concentrations (C-max). There was also no difference between corresponding Miles and Bayer formulations for C-max values determined with the metabolite data. Although none of the differences in time to peak concentrations (T-max) of nitrendipine or metabolite were found to be significant, the Bayer formulations appeared to reach peak concentrations somewhat earlier than the Miles formulations. In contrast, the suspension dose produced significantly higher C-max and AUC, and substantially shorter T-max values than any of the tablet formulations. Although this study involved administration of an acute dose to normotensive volunteers, the T-max values coincided with maximum decrease in systolic pressure, and a relationship between nitrendipine concentration and decrease in systolic pressure was observed with tablet formulations. This study also yielded additional data on terminal nitrendipine elimination half-life. Terminal elimination half-lives, ranging from 16.5 to 30.9 h, were observed using a sensitive capillary GC procedure and 14–48 h postdose mean plasma concentrations.

The effects of age and race on nitrendipine pharmacokinetics and pharmacodynamics.

The pharmacokinetics and pharmacodynamics of a single 20-mg dose of nitrendipine (NTP) were studied in four groups of subjects (n = 9 per group). Group 1 were young white normotensive males, Group 2 were elderly white hypertensive males, Group 3 were black hypertensive males aged 40-55 years, and Group 4 were white hypertensive males aged 40-55 years. All other medications were withdrawn prior to NTP dosing. NTP was given in the morning 1 h after breakfast. Plasma samples for NTP assay were collected at predetermined times up to 48 h after dosing. Blood pressure was monitored before dosing, and at 0.5, 1, 3, 5, 12, and 24 h postdose. Pharmacokinetic parameters were found to be dependent on age. The area under the curve for Groups 1, 2, 3, and 4 was 50.5 +/- 19.4, 186 +/- 120, 107 +/- 49, and 88 +/- 43 ng h/ml, respectively (p less than 0.05). Corresponding values of elimination half-life were 9.9 +/- 1.3, 20 +/- 6.5, 13.3 +/- 6.1, and 15.9 +/- 8.0 h (p less than 0.05). Both diastolic and systolic blood pressures were significantly reduced from the baseline value in Groups 2, 3, and 4, with diastolic pressure remaining significantly lower than baseline at 24 h postdose. Based on the increased plasma levels and slower elimination of NTP in the elderly, as well as the measured blood pressure lowering, once daily dosing of NTP may be appropriate in some patients.

Influence of renal function on the pharmacokinetics of cerivastatin in normocholesterolemic adults.

AbstractObjective: The influence of impaired renal function on the pharmacokinetics of single and multiple doses of cerivastatin was evaluated in this non-randomized, non-blinded, 7-day, multiple-dose study. Methods: Thirty-five adults between the ages of 21 years and 75 years with normal renal function (CLCR >90 ml/min/1.73 m2, n=9), or patients with either mild (CLCR 61 ml/min/1.73 m2 to ≤90 ml/min/1.73 m2, n=9), moderate (CLCR 30 ml/min/1.73 m2 to ≤60 ml/min/1.73 m2, n=8), or severe (CLCR <30 ml/min/1.73 m2, but not on dialysis, n=9) renal impairment were given cerivastatin 0.3 mg daily each evening for 7 days. The steady-state pharmacokinetics of cerivastatin, including the area under the concentration–time curve (AUC)0–24, peak plasma concentration (Cmax), time to reach Cmax (tmax) and elimination half-life (t1/2), were determined on day 1 and day 7. The logarithm of the pharmacokinetic variables was analyzed using analysis of variance (ANOVA). Safety assessments included physical examination, fundoscopy, vital signs, electrocardiogram (ECG), adverse events, and laboratory safety indices. Results: The day-1 AUC in patients with mild renal impairment was similar to that of patients with normal function (19.6 μg/h/l vs 19.2 μg/h/l, respectively). However, the AUC for cerivastatin patients with moderate or severe renal impairment was 40–60% higher (30.8 μg/h/l and 29.0 μg/h/l, respectively). Cmax values for patients with normal, mild, moderate, and severe renal impairment were 3.3, 3.4, 4.6, and 5.2 μg/l, respectively. This modest increase in plasma cerivastatin levels is nearly equivalent to a 0.4-mg daily dose, which has been recently approved in the United States. The mean t1/2 of cerivastatin was less than 4.5 h in all patients, indicating that renal dysfunction did not promote cerivastatin accumulation. This observation was confirmed by the finding that the cerivastatin plasma levels on day 1 and day 7 were similar in all patient groups. Furthermore, the mean AUC and Cmax values for both demethylated and hydroxylated cerivastatin were similar in the patients with the most severe renal dysfunction to the corresponding values in healthy subjects. Cerivastatin was well tolerated in all patients irrespective of renal function. Adverse events were observed in 37% of the subjects; nearly all were mild and generally of short duration, and most resolved without intervention. Incidence of adverse events was similar across all three renal groups and the control group. There were no clinically significant laboratory changes other than those consistent with renal disease. Conclusion: This study demonstrates that dosage adjustment of the daily 0.3-mg cerivastatin dose in patients with significant renal impairment is likely unnecessary.

Effects of Beano on the tolerability and pharmacodynamics of acarbose

Acarbose is an alpha-glucosidase inhibitor approved for the treatment of type 2 diabetes mellitus. Acarbose inhibits carbohydrate digestion, allowing an excessive amount of undigested carbohydrate to reach the colon. Bacterial fermentation of the carbohydrate produces intestinal gas, which can cause flatulence and abdominal pain. Beano, an over-the-counter enzyme preparation (alpha-galactosidase), diminishes intestinal gas production by enhancing the breakdown of certain carbohydrates before they reach the lower intestine. This study was undertaken to investigate whether concomitant administration of Beano and acarbose could reduce the flatulence associated with acarbose and, if so, whether Beano would interfere with the effects of acarbose on postprandial serum glucose concentration. In this randomized, double-masked, placebo-controlled, three-period crossover study, 37 patients with type 2 diabetes mellitus received acarbose 100 mg, acarbose 100 mg plus Beano, or placebo. The study population consisted of 20 males and 17 females who ranged in age from 36 to 72 years (mean, 56 years) and in weight from 62 to 142 kg (mean, 92 kg). Each treatment period consisted of 3 days, during which both acarbose and Beano were given at the beginning of each of three meals. There was a 4-day washout interval between each treatment period. The frequency and severity of flatulence were measured using a score compiled from patient diaries. As an additional measure of intestinal gas production, breath hydrogen concentration was measured on day 3 of each treatment period. Postprandial serum glucose concentration was measured at predetermined times after each morning dose to assess pharmacodynamic activity. Patients who took Beano with acarbose had a significantly lower flatulence score than did those who took acarbose alone (0.79 vs 1.09). Consistent with this finding, breath hydrogen concentration was lower after administration of acarbose plus Beano than with acarbose alone (31.2 ppm vs 50.5 ppm). Beano had variable effects on the ability of acarbose to reduce the postprandial serum glucose concentration. Although postprandial serum glucose levels were higher in patients who received acarbose plus Beano than in those who received acarbose alone, both treatments (with or without Beano) resulted in postprandial serum glucose levels that were significantly lower than those seen with placebo. Therefore, although Beano appeared to diminish the activity of acarbose, postprandial serum glucose concentrations still decreased significantly in patients taking Beano with acarbose. Beano has been shown to alleviate the flatulence accompanying acarbose treatment, but it may also interfere with the glucose-lowering effect of acarbose.