Carisoprodol Single and Multiple Dose PK-PD. Part II: Pharmacodynamics Evaluation Method for Central Muscle Relaxants. Double-Blind Placebo-Controlled Clinical Trial in Healthy Volunteers.

Centrally acting skeletal muscle relaxants (CMR) such as carisoprodol are used to treat acute, painful musculoskeletal conditions, though its precise mode of action has not been characterized. A double-blinded, placebo-controlled, randomized clinical trial was designed to evaluate the pharmacokinetics-pharmacodynamics (PKPD) of CMR after single (350 mg), double (700 mg), and multiple doses (up to 350 mg/8 h, 14 days) of carisoprodol. Muscular (Electromyogram-EMG, muscular strength dynamometry), central (sedation), and tolerability (psychomotor activity test, adverse events) parameters, as well as withdrawal symptoms, were evaluated. Thirteen healthy volunteers were enrolled. No evidence of direct muscle relaxation was evidenced, but some differences on sedation were evidenced throughout the study, suggesting that CMRs act, at least partly, through sedation. Most significant differences were detected at 1.5 h after dosing. The effect on psychomotor impairment was variable, most prominently after 1.5 h, too, suggesting that it is produced by carisoprodol rather than by meprobamate. No withdrawal symptoms were detected, so the risk of dependence following maximum doses and duration of treatment recommended, and under medical supervision, should be low.

Effect of enantiomerism on the bioequivalence of a new ibuprofen 600-mg tablet formulation obtained by roller compaction.

The bioequivalence of a new ibuprofen 600-mg film-coated tablet obtained by roller compaction was studied in a crossover study with 22 healthy volunteers. Bioequivalence was analyzed based on (a) the S-enantiomer, (b) the R-enantiomer, and (c) the sum of both enantiomers (representing the results of an achiral assay). The bioequivalence conclusion for ibuprofen products should be based not only on AUC and Cmax but also on tmax since tmax is related to the onset of action. However, it is not possible to ensure if bioequivalence has been demonstrated for tmax as regulators have not defined the acceptance range for the difference between medians of tmax in those cases, where tmax is clinically relevant. In this study, it was possible to conclude bioequivalence for tmax based on S-ibuprofen, though this conclusion might be questioned if the decision is based on R-ibuprofen or the achiral method.

Effect of Roux-en-Y gastric surgery on ciprofloxacin pharmacokinetics: an obvious effect?

PURPOSE: To evaluate pharmacokinetic parameters of ciprofloxacin in patients undergoing Roux-en-Y gastric surgery (RYGS). METHODS: Controlled, single-dose, open-label study in patients undergoing RYGS. Healthy overweight/obese patients 18-60 years old were included. The assessment was performed once in control patients and three times in case patients (before surgery and 1 and 6 months after surgery). In each visit, the subjects received a single oral dose of ciprofloxacin 500 mg. Venous blood samples were obtained at baseline and 0.5, 1, 1.25, 1.5, 1.75, 2, 2.5, 3, 4, 8 and 14 h after ciprofloxacin intake. Pre- and post-surgery variables were compared using paired ANOVA or the Wilcoxon tests and control vs cases using ANOVA or Mann Whitney. Given the post-surgery change in body weight, the parameters were corrected by dose (mg)/body weight (kg). The analysis was performed using SPSS. RESULTS: Ciprofloxacin Cmax was significantly reduced 1 month after surgery (1840.9 ± 485.2 vs 1589.6 ± 321.8 ng/ml; p = 0.032) but not 6 months after. Cmax on the sixth month was lower than Cmax in control group (2160.4 ± 408.6 vs 1589.6 ± 321.8 ng/ml; p < 0.001). After correcting by the dose (mg)/patient's body weight, both Cmax and AUClast showed significant decrease 1 and 6 months after surgery: Cmax, 289.1 ± 65.3 and 263.5 ± 52.1 (ng/ml)/(dose (mg)/weight (kg)) respectively vs 429.3 ± 127.6 (ng/ml)/(dose (mg)/weight (kg)) at baseline; AUC, 1340.6 ± 243.0 and 1299.2 ± 415.4 (h × ng/ml)/(dose (mg)/weight (kg)) respectively vs 1896.7 ± 396.8 (h × ng/ml)/(dose (mg)/weight (kg)) at baseline. Cmax 1 month post-surgery showed lower values than the control group (375.4 ± 77.4 vs 263.5 ± 52.1 ng/ml; p < 0.001). CONCLUSION: Ciprofloxacin absorption is impaired 1 month and 6 months after RYGS. The effect on Cmax and AUClast faded on the sixth month due to weight loss. It is no necessary to modify the doses of ciprofloxacin in these patients.

Effect of drug-test interactions on length of hospital stay.

PURPOSE: To evaluate the impact of drug-laboratory test interactions on the length of stay of hospitalised patients. METHODS: Observational study of 404 discharges from the Internal Medicine Services of a tertiary hospital. Databases with information on general data, medication and tests performed were linked with the potential interactions described in the literature. This revealed the potential interactions between drugs and laboratory tests (PIDL) in each patient. Several linear regression models, adjusted for confounders, were performed to test the effect of both the number of PIDL and their influence on tests results (false positive/negative) on the length of stay. RESULTS: A total of 19 741 PIDL were detected; 5954 could give rise to potential false positive (PFP) results and 8442 to potential false negative (PFN) ones. Each PFP was related to an increase of 0.051 days in stay duration (CI95% 0.001-0.102) and each PFN to 0.045 days (CI95% 0.008-0.081). Globally, 303 and 380 days of hospitalisation could be attributed to false positives and false negatives, which could account for 9.8% of the total stay of these patients. CONCLUSIONS: These results show that the interactions between drugs and laboratory tests produce a statistically and clinically significant increase in the duration of hospital stay.

Comparative bioavailability/ bioequivalence of two different sertraline formulations: a randomised, 2-period x 2-sequence, crossover clinical trial in healthy volunteers.

An open-label, randomised, crossover single dose study, using 2 periods x 2 sequences, with a minimum washout period of 4 weeks, was conducted in order to assess the comparative bioavailability of two formulations of sertraline hydrochloride (CAS 79617-96-2) 100 mg tablets. Plasma samples were obtained at intake (baseline) and at +1 h, +2 h, +3 h, +4 h, +5 h, +6 h, +7 h, +8 h, +9 h, +12 h, +24 h, +48 h, +72 h and +96 h post administration. Sertraline plasma concentrations were determined by high pressure liquid chromatography with tandem mass detection (HPLC-MS/MS) and the lower limit of quantification was set at 100.15 pg/mL. Pharmacokinetic parameters used for bioequivalence assessment (AUClast, AUCinf and Cmax) were determined by non-compartmental analysis. Classical 90 % confidence intervals (90CI) were calculated for the overall sample, and for males and females separately, and gender effects were investigated using an appropriate model. The results showed that overall classical 90CI were 84.55-100.32 % for Cmax 86.96-98.68 % for AUClast, and 86.79-98.93 for AUCinf, that is, they were all within the predefined ranges for bioequivalence acceptance. Separate gender analysis showed very similar results for males and females when analysed independently, and no gender effects were detected in bioequivalence analysis (p > 0.05). It may be therefore concluded that the evaluated formulations are bioequivalent in terms of rate and extent of absorption.

Bioequivalence study of two different tablet formulations of carvedilol in healthy volunteers.

OBJECTIVE: The aim of this study was to compare the extent and rate of absorption of two different carvedilol (CAS 72956-09-3) tablet formulations: 25 mg tablets, as the test formulation and the reference innovator product (25 mg tablets). METHODS: This study was designed as a single-dose, open-label, randomised, with a two-period and two-sequence crossover design, with blind determination of drug plasma concentration and a minimum 7-day washout period. Twenty-four healthy volunteers of both sexes were randomly assigned to treatment sequences. Carvedilol concentrations were determined in plasma samples obtained over a 24-h interval: baseline (pre-administration) and at 14 different times within the 24 h after administration. The analytical method, which used HPLC coupled with a MS/MS detector, was duly validated and the analytical assay was performed in compliance with Good Laboratory Practice (GLP). The limit of quantification (LOQ) was 0.50 ng/mL. Pharmacokinetic parameters representing the extent and/or rate of absorption (AUCinf, AUClast, and Cmax) were obtained. As secondary objective the tolerability of both formulations was also evaluated. RESULTS: The geometric mean of the test/reference formulations individual percent ratio was 98.14 % for AUCinf, 98.44 % for AUClast and 98.39 % for Cmax. The 90 % CI for the geometric mean of the individual ratio test/references formulations was 95.13 to 101.24 % for AUCinf, 95.23 to 101.76 % for AUClast, and 88.26 to 109.67 % for Cmax. CONCLUSIONS: The 90 % CI values obtained for AUCinf, AUClast, and Cmax are within the interval proposed by the EMEA/CPMP and the FDA as bioequivalence acceptance criteria, and consequently it can be conclude that the test formulation is bioequivalent with the reference formulation both in terms of rate and extent of absorption after single dose administration. The results from a previous pilot study allowed an optimal design for this trial.

Truncated AUC in the evaluation of fluconazole bioequivalence. A cross-over, randomised, open-label study in healthy volunteers.

The bioequivalence of two capsule formulations (test and reference) containing 200 mg fluconazole (CAS 86386-73-4) was assessed in 24 healthy volunteers in an open, randomised, crossover, 2 periods x 2 sequences single dose study with a minimum washout period of 14 days. Plasma samples were obtained over 168 h (at baseline, 1 h, 2 h, 2.5 h, 3 h, 3.5 h, 4 h, 5 h, 6 h, 8 h, 12 h, 24 h, 48 h, 72 h, 120 h and 168 h after administration) and fluconazole concentrations were determined by means of an HPLC-WV method (limit of quantification: 0.2 microg/mL). Pharmacokinetic parameters used for bioequivalence assessment (AUClast, AUCinf and Cmax) were determined from the fluconazole concentration data using non-compartmental analysis. The results showed that all 90% confidence intervals (obtained by ANOVA) were 100.89-110.24 for Cmax, 99.07-107.35 for AUClast and 95.42-105.17 for AUCinf, that is, all within the predefined ranges. Furthermore AUCs truncated at 24, 48, 72 and 120 h were also within the 80-125% range. It may be therefore concluded that the evaluated formulations are bioequivalent in terms of rate and extent of absorption.

Bioequivalence study of two formulations of enalapril, at a single oral dose of 20 mg (tablets): A randomized, two-way, open-label, crossover study in healthy volunteers.

BACKGROUND: Enalapril maleate is the monoethyl ester prodrug of enalapril- at, an angiotensin-converting enzyme inhibitor indicated in the management of essential and renovascular hypertension, and in the treatment of congestive heart failure and in asymptomatic patients with left ventricular dysfunction and an ejection fraction of ≥35%. Enalapril has little pharmacologic activity until hydrolyzed in vivo to enalaprilat. OBJECTIVE: The aim of the present study was to compare the bioavailability and tolerability of 2 commercial brands (test and reference formulations) of enalapril tablets (20 mg), described as the rate and extent of absorption of the active moiety, to assess their bioequivalence. METHODS: This single-dose, randomized, 2-way, open-label, crossover study in healthy volunteers aged 18 to 40 years was conducted at the Clinical Pharmacology Study Unit, Hospital Clínico San Carlos (Madrid, Spain). Subjects were randomized to receive (under fasting conditions) either the test or reference formulation of enalapril (20-mg tablet) at study period 1 and the opposite formulation at study period 2. Study periods were separated by a washout period of at least 7 days. During each study period, 15 plasma extractions were made to determine enalapril and enalaprilat plasma concentrations and to calculate the pharmacokinetic (PK) properties (maximal plasma drug concentration [Cmax], time to Cmax [Tmax], area under the plasma concentration-time curve [AUC] to the last measurable concentration [AUCt], AUC from time 0 to infinity [AUC0-∞], mean residence time, and elimination half-life [tl2]) of both. Physical examination, subject interview, laboratory analyses, electrocardiogram, and blood pressure (BP) were used to assess tolerability. RESULTS: Twenty-four subjects were included in the study (12 men, 12 women; mean [SD] age, 22.8 [2.2] years [range, 19-30 years]). Of these, 1 subject (4.2%) withdrew from the study for personal reasons; thus, PK and statistical analyses included results from 23 subjects. No statistically significant sequence or period effect was found. Tmax was not statistically different between the 2 formulations, and the 90% CI calculated for Tmax for the difference of the medians was within the predefined range. The 90% CIs of the logarithmically transformed concentration-derived parameters (Cmax AUCt, and AUC0-∞) also were within the predefined range; thus, the 2 formulations are considered bioequivalent. For both formulations, systolic and diastolic BPs showed significant reductions compared with baseline values (P < 0.05). Seven adverse effects were recorded, all of them transient and none of severe intensity. CONCLUSIONS: In this study of 2 commercial brands (test and reference formulations) of enalapril in healthy subjects, designed and conducted under Good Clinical Practice guidelines, a similar rate and extent of absorption for both formulations were found to be bioequivalent. Both formulations produced a significant decrease in BP values and were generally well tolerated.

Effect of adverse drug reactions on length of stay in surgical intensive care units.

OBJECTIVE: To determine the frequency of adverse drug reactions in surgical intensive care units and evaluate their effect on the length of stay. DESIGN: Prospective cohort study. Between May 1997 and December 1999, while the patients were staying in the surgical intensive care unit, data were gathered regarding suspected adverse drug reactions and on different variables related to the length of stay. SETTING: Surgical intensive care units of our hospital. PATIENTS: A total of 401 patients hospitalized in the surgical intensive care unit. MAIN RESULTS: In 37 of the 401 patients seen (9.2%; 95% confidence interval, 6.6-12.5), 39 different adverse drug reactions were detected. The adverse drug reactions were most frequently caused by the following drugs: morphine hydrochloride (n = 13), meperidine hydrochloride (n = 9), and metamizole (n = 7). Five adverse drug reactions were severe, the suspected medication had to be discontinued in 14 cases, and new drugs were necessary to manage the adverse drug reaction in 28 cases. The crude estimation of the effect of adverse drug reactions performed on the length of stay with a bivariant regression model indicated that each adverse drug reaction was related to an increase of 3.39 days (95% confidence interval, 1.47-5.31) in the length of stay. This estimation was reduced to 2.31 days (95% confidence interval, 0.64-3.99) when considering other variables that might cause confusion for analysis, although it is still important. CONCLUSIONS: Adverse drug reactions are a significant clinical and economic problem in surgical intensive care units.

A new high-absorption-rate Paracetamol 500-mg formulation: a comparative bioavailability study in healthy volunteers.

BACKGROUND: Paracetamol is often the analgesic or antipyretic of choice, especially for patients for whom salicylates or other nonsteroidal anti-inflammatory drugs are contraindicated. OBJECTIVE: The aim of this study was to compare the absorption rate of a new tablet formulation of paracetamol (500 mg) with a reference formulation of paracetamol at the same dose. METHODS: This was a single-center, Phase I, open-label, randomized, 2-period, crossover, single-dose, comparative bioavailability clinical trial. During both study periods, healthy volunteers were given a single oral dose of a more hydrophilic test formulation of paracetamol, or a reference formulation. Fifteen plasma samples were obtained to determine paracetamol concentrations and to calculate kinetic parameters. RESULTS: The study participants comprised 24 healthy volunteers (12 men, 12 women; mean [SD] age, 22.8 [1.5] years). The pharmacokinetic parameters calculated for the test versus the reference formulation were as follows: median time to maximum concentration (Tmax), 0.42 versus 0.75 hour; mean (SD) maximum plasma drug concentration (Cmax), 9.85 (2.40) µg/mL versus 8.33 (2.22) µg/mL; and mean (SD) area under the plasma concentration-time curve from time 0 to infinity (AUC0-∞), 30.16 (8.87) µg·h/mL versus 28.49 (8.57) µg · h/mL. The 90% CIs of the ratios were as follows: base e logarithm (Ln)-transformed Cmax, 105.08% to 137.59%; Ln-AUC0-∞, 102.02% to 110.43%; and the difference in Tmax, -0.375 to -0.085 hours. CONCLUSIONS: The speed of release and absorption was statistically significantly higher with the test formulation compared with the reference one (evaluated using Tmax, Cmax, and Cmax/AUC parameters). This speed is especially important for a rapid analgesic or antipyretic effect.