Pharmacokinetics and bioequivalence evaluation of three commercial tablet formulations of mefloquine when given in combination with dihydroartemisinin in patients with acute uncomplicated falciparum malaria

Objective: To assess the pharmacokinetics and relative bioavailability/bioequivalence of three commercial tablet formulations of mefloquine, i.e. Lariam (reference formulation), Mephaquin 100 Lactab and Eloquin-250, when given sequentially after dihydroartemisinin in Thai patients with acute uncomplicated falciparum malaria. Methods: Twenty-nine Thai patients with acute uncomplicated falciparum malaria were randomised to receive an initial dose of 300 mg dihydroartemisinin, followed by 1250 mg mefloquine (at 24 h and 30 h after dihydroartemisinin) given as either Lariam (n=10 cases), Mephaquin (n=9 cases) or Eloquin-250 (n=10 cases). Serial blood samples were obtained up to day 42 after treatment with mefloquine. Mefloquine concentrations were determined in whole blood by means of ultraviolet high-performance liquid chromatography. The pharmacokinetic parameters of mefloquine were estimated using non-compartmental and compartmental analysis. Results: The three combination regimens were well tolerated. Patients in all treatment groups had a rapid initial response. However, nine patients (four and five cases in regimen containing Mephaquin 100 Lactab and Eloquin-250, respectively) had reappearance of parasitaemia during the follow-up period. Mefloquine from the three formulations showed significantly different pharmacokinetic and bioavailability metrics. Significantly lower peak plasma concentrations (C_max) and areas under the plasma concentration–time curve (AUC; AUC_0–48h, AUC_0–7days, and total AUC) were observed with Mephaquin 100 Lactab than with the other two formulations. Mean values for relative bioavailability of the test to standard products were 49.1% (Mephaquin 100 Lactab) and 72.4% (Eloquine-250). Based on the criteria set, the bioavailability of the two test products (Mephaquin 100 Lactab and Eloquine-250) was considered non-equivalent to the reference product with respect to the rate (t_max, C_max) and extent (AUC_0–48h, AUC_0–7days, total AUC) of mefloquine absorption. Received: 15 June 1999 / Accepted in revised form: 7 October 1999     

Experimental, extrapolated and truncated areas under the concentration–time curve in bioequivalence trials

Objective: The extrapolated area under the concentration–time curve (AUC_0–∞) for any drug is considered by operating guidelines as the primary parameter related to the extent of absorption in single-dose bioavailability and bioequivalence trials. Not more than 20% should be added to the experimental AUC (AUC_0–t) in the extrapolating procedure. However, in certain specific cases, it is problematic and, in other cases, impossible to respect the above requirement. It was intended to demonstrate that truncated AUC or AUC_0–t would be used in bioequivalence trials when the AUC cannot be extrapolated. Methods: AUC_0–t and truncated AUC were compared at various time intervals with AUC_0–∞ in a series of 19 single-dose bioequivalence trials covering 15 different drugs, each carried out on 12–24 healthy volunteers. Point estimators and 90% confidence intervals in the 0.80–1.25 and 0.70–1.43 ranges were statistically processed using log-transformed parameters. Results: In all the trials considered, overlapping point estimators and 90% confidence intervals were invariably obtained, regardless of the AUC used. Conclusion: The use of AUC_0–t or truncated AUC may be considered an ancillary procedure in bioequivalence trials when AUC cannot be extrapolated. This occurs with most extended-release formulations, endogenous substances, and poorly absorbed drugs. It also occurs in trials with one or more poor metabolisers, with drugs possessing very long elimination half-lives, and with bioassays having problems of sensitivity that preclude sufficiently precise plasma concentration measurement over the required sampling period. Received: 16 June 1999 / Accepted in revised form: 3 August 1999     

Bioequivalence study of two enalapril maleate tablet formulations in healthy male volunteers Pharmacokinetic versus pharmacodynamic approach

Objective: Two different conventional release enalapril maleate tablet formulations were evaluated for their relative bioavailability (Eupressin tablets 10 mg, Biosintética as the test formulation vs Renitec tablets 10 mg Merck Sharp & Dhome, as the reference formulation). A single 20 mg oral dose of each preparation was administered to 18 healthy male adult volunteers and their bioequivalence was assessed by comparing the serum enalaprilat and total enalapril (enalaprilat plus enalapril maleate) concentration-time curves. Angiotensin converting enzyme (ACE) activity was also quantified in each serum sample. Results: The pharmacokinetic parameters obtained for each formulation were the area under the time-concentration curve from 0 to 24 h (AUC_[0–24]), maximum concentration C_max and the time at which it occurred (t_max). When serum enalaprilat concentration-time curves were employed to assess bioequivalence, the formulations were bioequivalent in the extent but not in the rate of absorption. However, no difference in either the extent or the rate of absorption were observed when serum total enalapril vs time curves were analysed. ACE activity-time curves were similar for both formulations and showed that ACE was 90% inhibited 3–5 h after enalapril administration, and till approximately 50% after 24 h. At that time, circulating enalaprilat and total enalapril levels were less than the tenth of C_max. Conclusion: The results show that complete bioequivalence of the two formulations can be concluded from serum total enalapril concentration data, and that serum ACE activity is not a suitable pharmacodynamic variable for assessing bioequivalence. Received: 29 May 1995/Accepted in revised form: 30 October 1995     

Population pharmacokinetic modelling of S-warfarin to evaluate the design of drug–drug interaction studies for CYP2C9

This study is to assess pharmacokinetic (PK) sampling time schedules and trial size requirements of drug–drug interaction (DDI) studies for CYP2C9, based on S-warfarin population PK models. S-warfarin plasma concentrations from eight DDI studies were utilized to develop S-warfarin population PK models. Optimal PK sampling times were obtained that minimized mean squared error of geometric mean of the area under the concentration–time curve (AUC_0−∞). The powers and type I error rates of testing the equivalences of the geometric means of AUC_0−∞ only and AUC_0−∞ and maximum concentration (C _max), jointly, were assessed via simulation for two-by-two cross-over designs. The results were compared to those from three bioequivalence sample size calculation methods. Two-compartment population PK models with first order absorption were established for non-Asian and Asian subjects. The optimal PK sampling times of size 17 per individual per period were found to be 0.0, 0.5, 1.0, 2.0, 4.0, 6.0, 10.0, 12.0, 16.0, 24.0, 36.0, 48.0, 60.0, 72.0, 96.0, 120.0, 144.0 h post a single oral dose of 25 mg warfarin. For non-Asian subjects, the minimum numbers of subjects required per trial with the optimal PK sampling schedule to achieve 80% power and 5% type I error rate, ranged from 6 to 19 for the equivalence of AUC_0−∞ and C _max jointly. It has been demonstrated that appropriately selected PK sampling time points can greatly increase the corresponding power of the study without increasing the number of subjects, especially when the true ratio is near the default bioequivalence boundary (0.8–1.25).     

Clinical efficacy, safety and pharmacokinetics of a newly developed controlled release morphine sulphate suppository in patients with cancer pain

Objective: To compare the efficacy, safety and pharmacokinetics of a newly developed controlled- release suppository (MSR) with MS Contin tablets (MSC) in cancer patients with pain. Methods: In a double-blind, randomised, two-way cross-over trial, 25 patients with cancer pain were selected with a morphine (M) demand of 30 mg every 12 h. Patients were divided into two groups. Group 1 received active MSC (30 mg) and placebo MSR, followed by placebo MSC and active MSR (30 mg) each for a period of 5 days. Group 2 started with active MSR and placebo MSC, followed by active MSC and placebo MSR, each for a period of 5 days. Blood for determination of plasma concentration of morphine (M) and its 3- and 6-glucuronides (M3G, M6G) was collected, and area under the plasma concentration–time curve (AUC)_0–12 h, peak plasma concentration (C_max), time to reach C_max (t_max), and C0 and C12 of M, M6G and M3G were determined on day 5 and day 10. Intensity of pain experienced by each patient was assessed every 2 h on a 0–10 scale, while side effects and rescue medication were recorded. Results: Twenty patients (ten patients in each group) completed the study. A pronounced inter-patient variability in plasma concentrations of M, M3G and M6G was observed after administration of both forms. Apart from the C0 and C12, no significant differences in AUC_0–12 h, t_max and C_max of morphine between the rectal and oral route of administration were found. In the case of the metabolites, it was found that AUC_0–12 h and C_max of M6G, and AUC_0–12 h, C_max, C0 and C12 of M3G after rectal administration were significantly lower than after oral administration. However, apart from the t_max of M6G, none of the pharmacokinetic parameters of M, M6G or M3G met the criteria for bioequivalence. There were no significant (P=0.44) differences in pain intensity score between the oral and rectal forms within the two groups, regardless of the treatment sequence. No treatment differences in nausea, sedation or the demand on escape medication (acetaminophen tablets) between the rectal and oral forms were observed. Conclusion: The newly developed controlled-release M suppository is safe and effective and may be a useful alternative for oral morphine administration in patients with cancer pain. Received: 3 September 1999 / Accepted: 15 March 2000     

Concomitant administration of the α-glucosidase inhibitor voglibose (AO-128) does not alter the pharmacokinetics of glibenclamide

Objective: Voglibose is a new and potent inhibitor of α-glucosidases used for treatment of diabetes mellitus. It increases gastro-intestinal motility and could thus affect absorption of other concurrently administered antidiabetic drugs. The aim of this study was to investigate whether or not voglibose modifies the pharmacokinetics of glibenclamide, a widely used oral antidiabetic, and the glibenclamide-induced decrease in fasting serum glucose. Methods: Twelve healthy male subjects were included in this double-blind cross-over study and received a single 1.75-mg dose of glibenclamide on the 8th day of continuous administration of either placebo (reference) or voglibose 5 mg t.i.d. (test). Blood samples were taken to determine the pharmacokinetic characteristics of gliben-clamide and the test/reference ratios were evaluated according to bioequivalence criteria. Additional blood samples were taken to measure serum glucose on the same day. Results: The concentration–time course of glibenclamide under concomitant voglibose administration was similar to that under placebo. The equivalence ratio (test/reference) for the pharmacokinetic characteristics AUC_normwas 1.03 (geometric mean; 0.95–1.11, 90% confidence interval) and C_max,norm1.01 (0.94–1.08). The parameters were within the accepted range of 0.8–1.25 (AUC) or 0.7–1.43 (C_max), thus fulfilling equivalence criteria and indicating no effect of voglibose on glibenclamide kinetics. The glibenclamide-induced decrease in fasting serum glucose concentration was similarly independent of placebo or voglibose co-administration. Conclusions: Voglibose did not interact with glibenclamide on a pharmacokinetic level. Concomitant treatment was well tolerated and has been proven to be safe for further clinical use. Received: 28 February 1997 / Accepted in revised form: 8 May 1997     

An Alternative Approach for Assessment of Rate of Absorption in Bioequivalence Studies

The partial area method was investigated for evaluation of equivalency in the rate of absorption of immediate release formulations. The applicability of the method was demonstrated with four drugs with different pharmacokinetic/pharmacodynamic characteristics. The confidence interval approach currently employed for bioequivalence determinations was applied to the relevant absorption parameters, including C _max and partial AUCs. The method was found to be more discriminating than C _max and/or T _max in the evaluation of the absorption rate of drugs. The cutoff time or point for partial AUC calculation may vary with the type of drug under study, depending on its clinical use and onset of action. The method was shown to be useful in the assessment of rate of absorption in bioequivalence studies.     

Bioavailability of intranasal formulations of dihydroergotamine

Objective: A comparison of the pharmacokinetic properties of two novel intranasal preparations of dihydroergotamine mesilate (DHEM) with a commercially available intranasal preparation. Methods: Two intranasal formulations of DHEM in combination with randomly methylated β-cyclodextrin (RAMEB) were prepared. Subsequently, in an open, randomised, crossover study in nine healthy volunteers, the following medication was administered: 2 mg DHEM/2% RAMEB nasal spray ( =two puffs of 100 μl); 2 mg DHEM/4 mg RAMEB nasal powder; 2 mg Diergo nasal spray ( =four puffs of 125 μl); 0.5 mg DHEM i.m., and 2 mg DHEM solution p.o. Results: No statistically significant differences were found in maximum plasma concentration (C_max), time to reach C_max (t_max), area under plasma concentration–time curve (AUC_0–8 h), Frel_(t=8 h) and C_max/ AUC_(t=8 h) for the three intranasal preparations. The relative bioavailabilities of the DHEM/RAMEB nasal spray, the DHEM/RAMEB nasal powder and the commercially available DHEM nasal spray were 25%, 19% and 21%, respectively, in comparison with i.m. administration. The relative bioavailability after oral administration was 8%. Conclusion: The pharmacokinetic properties of the novel intranasal preparations are not significantly different from the commercially available nasal spray. Advantages of the DHEM/RAMEB nasal spray are (1) less complicated handling, (2) reduction of the number of puffs and (3) a preference by the volunteers. Received: 12 February 1999 / Accepted in revised form: 23 August 1999     

Interchangeability of two 500 mg amoxicillin capsules with one 1000 mg amoxicillin tablet after a single oral administration

The aim of the study was to evaluate if two capsules (Amoxil^® capsules, 500 mg/capsule) and one tablet (Amoxicare^® tablets, 1000 mg/tablet) of amoxicillin have similar bioequivalence parameters. For this purpose a randomized, two-way, crossover, bioequivalence study was performed in 24 healthy, male volunteers, divided into two groups of 12 subjects each. One group was treated with the reference standard (Amoxil^®) and the other one with the generic tablet Amoxicare^®, with a crossover after a wash-out period of 7 days. Blood samples were collected at fixed time intervals and amoxicillin was determined by a validated HPLC method. The pharmacokinetic parameters AUC_0-8, AUC_0-∞, C_max, T_max, K_e and T_1/2 were determined for both formulations and statistically compared to evaluate the bioequivalence between the two brands of amoxicillin, using the statistical model recommended by the FDA. C_max and AUC_0-∞ were statistically analyzed using analysis of variance (ANOVA); no statistically significant difference was observed between the two formulations. The 90% confidence intervals between the mean values of C_max and AUC_0-∞ fall within the FDA specified bioequivalent limits (80-125%) suggesting that the two products are bioequivalent and the two formulations are interchangeable. Based on these findings it was concluded that the practice of interchangeability between the above formulations to achieve better patient compliance could be followed without compromising the extent of amoxicillin absorption.     

Comparison of pharmacokinetics of citalopram in healthy Asian Indian and Mexican volunteers

Randomized, two-way crossover, bioequivalence studies were conducted separately in healthy Mexican and Asian Indian volunteers. One tablet either of test or of reference product was administered after 10?h of overnight fasting. After dosing, serial blood samples were collected for a period of 72?h and 168?h, respectively, for both the studies. Plasma samples were analyzed for citalopram by a validated liquid chromatographic and mass spectrometric method (LC-MS/MS). The pharmacokinetic parameters AUC_0–t, AUC_0–72, AUC_0–∞, C_max, and T_max were determined from plasma concentration-time profiles for both the test and reference formulation of citalopram 20?mg tablets, and were compared statistically to evaluate bioequivalence between the two brands of citalopram. In both the studies, the analysis of variance (ANOVA) did not show any significant difference between the test and reference formulations and 90% confidence intervals (CI) were lying within the acceptable range for bioequivalence. The test and reference formulations exhibited comparable pharmacokinetics profiles and were bioequivalent, but high values of both C_max (~ 23%) and AUC (~ 34%) were observed in Asian Indian healthy volunteers as compared to the Mexican volunteers. This may be due to the poor metabolism of Citalopram in the Asian population. This difference in the results of pharmacokinetic parameters of Asian Indian and Mexican volunteers may be attributed to ethnic factors.     

Relative bioavailability and pharmacokinetics of two oral formulations of docosahexaenoic acid/eicosapentaenoic acid after multiple-dose administration in healthy volunteers

Objectives  To assess the comparative pharmacokinetic profile and bioavailability of docosahexaenoic acid (DHA)/eicosapentaenoic acid (EPA) after multiple-dose administration of a new oral formulation (test formulation) and a commercially available reference formulation in healthy subjects. Methods  Forty-eight healthy subjects received a 28-day oral treatment with DHA/EPA in the form of either the test or the reference product according to an open-label, randomized, parallel-group design. Both formulations were given t.i.d. at 8-h intervals at a dose of 3.0 g/day. Steady-state DHA and EPA concentrations in plasma and lysed whole blood were measured by gas-liquid chromatography at baseline and after 7, 14, 21 and 28 days of treatment. Kinetic parameters were compared both after subtraction of baseline concentrations and by using baseline concentrations as a covariate. Results  For both DHA and EPA, plasma and RBC concentrations measured from day 7 to day 28 were significantly higher than at baseline and did not differ significantly between the two products. On day 28 the plasma DHA concentration on average doubled the baseline level after administration of test and reference product, while there was a 10-fold increase in EPA plasma concentration. When the assessment was performed using baseline values as covariate, test-to-reference ratios for area under the curve (AUCss_0–8) and for peak concentration (Css_max) after the last administration on day 28 met bioequivalence criteria (i.e., 90% confidence intervals within 0.80–1.25 for AUCss_0–8 ratios, and within 0.75–1.33 for Css_max ratios). When the assessment was conducted after subtraction of baseline values, the 90% confidence intervals for Css_max ratios were within the bioequivalence range, whereas the intervals for AUCss_0–8 ratio were borderline for bioequivalence. Conclusion  The two formulations tested were similarly effective in increasing DHA and EPA concentrations in plasma and lysed whole blood, and showed comparable bioavailability for both active components.     

Comparison of several approaches of therapeutic drug monitoring of cyclosporin A based on individual pharmacokinetics

Objective: The clinical outcome of patients after organ transplantation is correlated with cyclosporin A (CyA) exposure. It is generally accepted that the area under the concentration–time curve (AUC) provides a reliable means for drug exposure. However, in routine therapeutic drug monitoring (TDM) of CyA, trough levels are mostly used. Currently, a number of different new concepts of CyA-TDM, including approaches such as single, double or triple time-point and abbreviated AUC determinations, have been introduced. The purpose of this study was to compare the predictive value of the different strategies of TDM. Methods: Calculations were based on 40 individual concentration–time profiles after oral administration of CyA to patients who had been included into an ongoing prospective clinical trial. Non-compartmental analysis was used to calculate the AUC_0–12h. Multiple linear regression was performed to describe the relationship between the different sets of blood concentrations and the respective AUC_0–12h as well as to evaluate their predictive value regarding AUC. Predictive performance was assessed by prediction bias and prediction precision, which were estimated as the mean prediction error and root mean squared error, respectively. Results: When comparing the various combinations of time points, it was found that one-point approaches showed the strongest differences with regard to the predictive value; the associated r² values differed from 0.203 to 0.792. The two and three time-point approaches showed lower differences – r² 0.802–0.972. The four-point and five-point approaches (r² 0.942–0.982) were the strongest predictors for CyA AUC_0–12h. Relative bias ranged from −27.7% to 63.8% and changed significantly when multiple-point predictors were used. In those cases, the predictive performance improved. Considering the predictive performance as well as the smallest bias and highest prediction precision, C3, C1 + C3, C1 + C3 + C6 and C1 + C2 + C3 + C6 were the best predictors. Conclusion: The results of this study indicate that in kidney transplant patients a clinically sufficient precise estimation of the CyA AUC is possible using two or three concentration–time points. Received: 18 November 1999 / Accepted in revised form: 10 February 2000     

Pharmacokinetic-pharmacodynamic modelling as a tool to evaluate the clinical relevance of a drug-food interaction for a nisoldipine controlled-release dosage form

Objective: Nisoldipine, a calcium antagonist of the dihydropyridine class, has been used in the treatment of hypertension and angina pectoris. A new controlled-release dosage form (nisoldipine coat-core, NCC) has been developed to allow once daily dosing. In addition to a formal food interaction study as requested by regulatory authorities for controlled-release dosage forms, a subsequent study was conducted to determine the clinical relevance of the changes in nisoldipine plasma concentration vs time profiles seen in the food effect study. Methods: After a placebo run-in phase of 6 days, 12 hypertensive patients started treatment with 20 mg NCC once daily (days 0–3, 5–6, 8–9). On days 4, 7 and 10 the NCC was substituted for 5, 10 and 20 mg nisoldipine solution, respectively, in order to obtain nisoldipine plasma concentration vs time profiles comparable to the ones resulting from the concomitant intake of food and NCC. Simultaneous measurements of blood pressure (BP) and nisoldipine concentration were performed on days 3, 4, 7 and 10. Results: The relationship between nisoldipine plasma concentrations and percentage reduction in BP [diastolic (DBP) and systolic (SBP), supine and standing] could be described by an E_max model. The mean maximum reduction (E_max) relative to baseline was about 36.4% and 37.7% (DBP, supine and standing) and 27.9% and 29.2% (SBP, supine and standing), respectively. The interindividual variability (% CV) in E_max was low, ranging from 17.6% to 28.8%. The mean nisoldipine plasma concentration corresponding to 50% of the maximum effect (EC₅₀) ranged between 0.99 and 2.62 μg · l^–1 with a pronounced interindividual variability (% CV) of 89.5–108.8%. Mean C_max values after administration of the 30 and 40 mg NCC together with food were 4.5 and 7.5 μg · l^–1, respectively. Based on the concentration-effect relationship established in the present study, the effect achieved with a concentration of 7.5 μg · l^–1 will be about 77% of E_max for DBP and about 88% of E_max for SBP, respectively. Conclusion: At the time of maximum plasma concentration the additional decrease in BP relative to baseline due to the food effect will be about 7–15% for DBP and 3–9% for SBP. After administration of the 10␣mg solution with a mean C_max of 8.7 μg · l^–1, only headache and flush with mild severity have been reported as adverse events. These maximum concentrations are comparable to C_max values seen after intake of 40 mg NCC with food. With regard to heart rate (HR) there were distinct differences between the two formulations: Following administration of 5, 10 and 20 mg nisoldipine solution, there were dose-dependent increases in HR by a maximum of 4, 12 and 16 beats · min⁻¹, respectively, whereas the HR profile for the NCC was similar to that seen under placebo treatment. Received: 28 December 1995 / Accepted in revised form: 19 August 1996     

Neoimmun versus Neoral: a bioequivalence study in healthy volunteers and influence of a fat-rich meal on the bioavailability of Neoimmun

In two crossover studies with 12 (6 males/6 females) healthy young volunteers each, we compared the bioavailability of Neoimmun capsules with the microemulsion Neoral and the influence of a fat-rich breakfast on the bioavailability of Neoimmun. Each volunteer received a single dose of 200 mg cyclosporine A in each period. Blood samples were taken up to 24 h and analysed for cyclosporine A by high-performance liquid chromatography (HPLC) and photometric detection. The pharmacokinetic parameters were determined by non-compartmental analysis. The treatments were tested for bioequivalence and significant differences. The bioavailability of Neoimmun was significantly lower compared to Neoral, albeit Neoimmun met the bioequivalence criterion (90% confidence interval of AUC 0.80–0.94) or missed the criterion only marginally (90% confidence interval of c _max 0.75–0.91). The bioavailability of Neoimmun as determined by area under the blood concentration-time curve (AUC) increased by nearly 20% after a fat-rich breakfast. However, mean peak concentrations after food were only higher in male subjects, whereas mean peak concentrations in female subjects were lower compared to fasting administration. In conclusion, our data show that Neoimmun exhibits a lower bioavailability than the microemulsion Neoral and that food has a significant but variable and sex-dependent impact on the bioavailability of Neoimmun capsules.     

Pharmacokinetic interactions between microemulsion formulated cyclosporine A and diltiazem in renal transplant recipients

Objective: Bilateral cyclosporin A (CsA) and diltiazem pharmacokinetic interactions have previously been investigated, however, not with the new microemulsion preconcentrate formulation of CsA (Sandimmun Neoral). In addition, the pharmacokinetic effects on the pharmacological active metabolites of diltiazem have not previously been investigated. We performed a pharmacokinetic interaction study in renal transplant recipients, measuring both unmetabolised CsA and diltiazem in addition to three of the main metabolites of diltiazem (M_A, M₁, M₂). Methods: Nine CsA-treated renal transplant patients were treated with diltiazem, 90–120 mg b.i.d., for 4 weeks. Pharmacokinetic investigations were performed both before and at the end of the diltiazem treatment period. Six non-CsA-treated renal transplant patients served as controls of CsA interactions with diltiazem and its metabolites. Results: Diltiazem treatment resulted in a significant mean increase in the area under the concentration–time curve (AUC) for CsA of 51(8)% (P < 0.008) and a peak concentration (C_max) of 34(8)% (P < 0.05), without altering time to peak concentration (t _max). CsA, however, did not significantly influence diltiazem pharmacokinetics, though two of the metabolites (M₁ and M₂) tended to be increased. Conclusions: Diltiazem interacts significantly with the pharmacokinetics of CsA in the new microemulsion formulation. Microemulsion-formulated CsA, however, did not show significant interaction with diltiazem pharmacokinetics. Received: 21 September 1998 / Accepted in revised form: 18 February 1999     

Pharmacodynamic properties and bioequivalence of dalteparin sodium subcutaneous injection in healthy Chinese male subjects

1.?Dalteparin sodium (DS) is a low molecular weight heparin that is widely used in the treatment of thromboembolism. The purpose of this study was to compare the pharmacodynamic properties and bioequivalence of the two formulations of DS with subcutaneous injection in healthy Chinese male subjects.

2.?In this randomized, open-label, two-period crossover study, a total of 24 male subjects were recruited to receive single subcutaneous doses of test and reference DS injection in two different sequences (12 subjects each) with a seven-day washout period. Plasma samples were obtained at different time points after administration of the injection and measured by chromogenic substrate assay. The pharmacodynamic parameters including E_max, AUEC_0–T, AUEC_0–∞ and T_max were analyzed to evaluate the bioequivalence of two DS formulations.

3.?The relative bioequivalence was 107.7?±?15.5 and 106.6?±?29.8 for Anti-Xa and Anti-IIa, two major active metabolites of DS, respectively. The 90% confidence intervals (CIs) of the geometric mean ratio (test/reference) of E_max, AUEC_0–T and AUEC_0–∞ were 98.71–104.40%, 101.95–112.13% and 102.38–112.10% for Anti-Xa, and 100.88–110.42%, 95.76–112.62% and 92.24–111.32% for Anti-IIa, respectively, and all of the 90% CIs were within 80–125%. The T_1/2 of reference and test were 2.88?±?1.21?h and 2.76?±?0.97?h for Anti-Xa, 1.87?±?0.62?h and 1.96?±?1.52?h for Anti-IIa.

4.?Based on the pharmacodynamic parameters and FDA Guidance on DS and regulatory criteria for bioequivalence, the test and reference formulations were bioequivalent in healthy Chinese male subjects.     

Bioavailability evaluation of two ceftriaxone formulations using two way crossover design in volunteers

For the bioequivalence study of two ceftriaxone injection formulations (Rocephin^®; Roche, and Triaxone^®; Hanmi), the HPLC analytical method for the analysis of ceftriaxone in plasma was used. Fourteen healthy volunteers completed the study and each subject were IM injected single doses (1 g) of the test and the reference formulations in a two-way crossover design with an one week drug free interval between doses. Following each administration, plasma concentrations of ceftriaxone were monitored over a period of 24 h. Bioequivalence parameters AUC_24h, T_max, C_max and MRT determined from the data obtained for the two formulations were examined by analyses of variance (ANOVA) and other criteria and tests for bioequivalence. Results of ANOVA and confidence limits of test/reference ratios of AUC_24h, T_max, C_max and MRT, and statistical tests indicated the bioequivalence of the two formulations (i. e., test/reference ratio was within 100±20%) except for T_max. The mean of T_max showed only 6. 9% difference from the reference but the detection limit was 22.5% which is slightly over the 20% criteria. No pharmacokinetic parameters including Ka, Kel, Vd and Cl indicated sigificant difference in between the two formulations. It was concluded that the data yielded for the two ceftriaxone formulations demonstrated that they were bioequivalent.     

Pharmacokinetics and Bioequivalence of Two Amoxicillin 500 mg Products: Effect of Food on Absorption and Supporting Scientific Justification for Biowaiver

PurposeAims of this study were to compare the bioequivalence of two formulations of amoxicillin 500 mg capsules under fasted and fed conditions in the same set of healthy volunteers, compare pharmacokinetics of amoxicillin under the two conditions and to assess the possibility of predicting in vivo bioequivalence of the two formulations using in vitro dissolution data.MethodThe innovator product of amoxicillin was used as the reference formulation and a test product, which showed in vitro equivalence after a biowaiver study with the same reference product was used in the bioequivalence study. Altogether 16 subjects were randomized to the reference and test products in the fasted study and 12 of them participated in the fed study. Plasma concentration of amoxicillin was analyzed by a validated Liquid chromatography coupled with two mass spectrometry (LC-MS/MS) method. Noncompartmental analysis was used to determine the pharmacokinetic parameters. Average bioequivalence method was used to evaluate the bioequivalence of the two formulations and statistical significance of the pharmacokinetic parameters were tested to study the effect of food on amoxicillin absorption.ResultsThe Geometric Mean Ratio (GMR) for the test/reference product for the maximum drug concentrations (C_max) was 102.77% and 97.38% in fasted and fed conditions respectively which was within 80.00–125.00% range required to demonstrate bioequivalence. The GMR for test/reference products for the area under the curve (AUC_0-8,) was 100.05% and 96.91% in fasted and fed conditions respectively meeting the bioequivalence criteria. For the reference product, the C_max was 9.38 and 7.61 µg x mL⁻¹(p =0.0224), time to reach maximum concentration (T_max) was 1.73 and 3.02 h (p=0.0005) and AUC_0-8 was 26.02 and 25.54 µg/h⁻¹ mL⁻¹ p = 0.672) under fasted and fed conditions respectively.ConclusionThe test and the reference formulations were bioequivalent under both fasted and fed conditions. Although the C_max was significantly lower and T_max was significantly delayed under fed conditions, it did not affect the AUC. Therefore, being a time dependent antibiotic, clinically significant effect of food on efficacy of amoxicillin is unlikely. As the selected products were equivalent in vitro, these findings support scientific justification for conducting in vitro dissolution studies for solid oral amoxicillin products as a surrogate for in vivo bioequivalence studies.     

Prediction of Pharmacokinetic Parameters and the Assessment of Their Variability in Bioequivalence Studies by Artificial Neural Networks

Purpose. The methodology of predicting the pharmacokinetic parameters (AUC, c_max, t_max) and the assessment of their variability in bioequivalence studies has been developed with the use of artificial neural networks. Methods. The data sets included results of 3 distinct bioequivalence studies of oral verapamil products, involving a total of 98 subjects and 312 drug applications. The modeling process involved building feedforward/backpropagation neural networks. Models for pharmacokinetic parameter prediction were also used for the assessment of their variability and for detecting the most influential variables for selected pharmacokinetic parameters. Variables of input neurons based on logistic parameters of the bioequivalence study, clinical-biochemical parameters, and the physical examination of individuals. Results. The average absolute prediction errors of the neural networks for AUC, c_max, and t_max prediction were: 30.54%, 39.56% and 30.74%, respectively. A sensitivity analysis demonstrated that for verapamil the three most influential variables assigned to input neurons were: total protein concentration, aspartate aminotransferase (AST) levels, and heart-rate for AUC, AST levels, total proteins and alanine aminotransferase (ALT) levels, for c_max, and the presence of food, blood pressure, and body-frame for t_max. Conclusions. The developed methodology could supply inclusion or exclusion criteria for subjects to be included in bioequivalence studies.     

Pharmacokinetics of oral entacapone after frequent multiple dosing and effects on levodopa disposition

Objective: Entacapone is a peripherally acting catechol O-methyltransferase (COMT) inhibitor used as an adjunct to each daily levodopa/dopa decarboxylase (DDC) inhibitor dose in the treatment of Parkinson's disease. Parkinsonian patients with advanced disease and motor fluctuations take several doses of levodopa daily, due to the short action of levodopa in this patient population. The present study was conducted in order to evaluate the pharmacokinetics of entacapone after multiple dosing and the pattern of COMT inhibition in erythrocytes during the first day of dosing as well as during steady state. Furthermore, the disposition of plasma levodopa and carbidopa was studied after a single dose of levodopa/carbidopa during the same conditions. Methods: Twelve healthy male volunteers received 200 mg entacapone eight times daily during study day 1 and day 6 at 2-h intervals from 0800 hours to 2200 hours. During days 3, 4 and 5, 200 mg of entacapone was taken ten times daily, from 0800 hours to 0200 hours on the following day. One levodopa/carbidopa tablet (100/25 mg) was taken on study day 1 and day 6 at 1000 hours. Plasma entacapone concentrations and erythrocyte COMT activities were measured frequently on study days 1–2 and 6–7, and twice daily on study days 3–5. Pharmacokinetic parameters calculated from plasma drug concentrations on days 1–2 and 6–7 were compared with each other. Results: There were no differences in maximal plasma concentration (C_max), time to maximal drug concentration in plasma (t_max), elimination half-life (t_1/2) and area under the plasma concentration–time curve (AUC) of entacapone between day 1 and day 6. The mean t_1/2 values of entacapone were 1.3 h and 1.8 h during the first and sixth days, respectively; the difference was not significant. No signs of accumulation of entacapone were noted after the first day. Entacapone reduced erythrocyte COMT activity after the first dose, and this effect was quite stable during frequent dosing. There were no indications of accumulation of COMT inhibition during frequent dosing of entacapone. There were no between-day differences in C_max, t_1/2 (2.4 h on days 1–2 and 2.3 h on days 6–7) or AUC of levodopa, whereas t_max occurred at 0.8 h on day 1 and at 1.2 h on day 6 (P = 0.03). There were no between-day differences in the pharmacokinetic parameters (C_max, t_max and AUC) of carbidopa. Conclusion: Even when dosed frequently, there are neither indications of accumulation of entacapone nor of its COMT inhibiting activity. Received: 28 December 1998 / Accepted in revised form: 29 March 1999