Maximum Plasma Drug Concentration Research Articles

Influence of Feeding and Analytical Method on the Bioequivalence of a Racemic Drug Undergoing Enantioselective Enterohepatic Recycling

Two crossover bioequivalence trials of an enantioselectively enterohepatic recycled drug, carprofen, were conducted in dogs with the same racemic oral formulation to determine: (i) the influence of feeding patterns, and (ii) the effect of the analytical method (enantioselective vs non-enantioselective) on the statistical power of the trials. The first trial was conducted with a standard feeding protocol and the second with a special feeding protocol selected to ensure constant biliary flow into the duodenum. Using a non-enantioselective technique, 90% confidence intervals provided conclusions of bioequivalence in 100% of the cases for both area under the plasma concentration versus time curve (AUC) and maximum plasma drug concentration (Cmax) with the special feeding protocol, but only 50% for AUC and 13% for Cmax with the standard feeding protocol, suggesting that a feeding pattern that diminishes plasma drug concentration rebound for an enterohepatically recycled drug increases the power of a bioequivalence trial. Whatever the feeding protocol, an enantioselective method decreased the power of the trials for AUC but increased the power of the trials for Cmax. For an enterohepatically recycled drug, feeding pattern can influence the power of a bioequivalence trial, and the analytical technique that provides the greatest power depends on the assessed bioequivalence parameter and the feeding pattern. © 2004 Wiley-Liss, Inc. and the American Pharmacists Association

Pharmacokinetics of ranitidine and nizatidine in very elderly patients

Purpose Histamine H2-antagonists, ranitidine and nizatidine, are frequently used for the treatment of hyperacidity and peptic ulceration. Although these agents are mainly eliminated by renal route, the fraction of renal clearance of ranitidine (70%) was greater than that of nizatidine(60%). This study was undertaken to examine whether the pharmacokinetic profiles of ranitidine and nizatidine differed during a repeated dosing in very elderly patients (>80 years old). Methods Ranitidine (150mg) or nizatidine (150mg) was given twice a day in 10 female very elderly patients (mean CLcr 67 ml/min) for 14 days. This study was performed by a randomized, cross-over design with a wash-out period of 14 days. Pharmacokinetic profiles were determined after 1st (on day 1) and 27th (on day 14) dosings of each agent. Results The maximum plasma drug concentration (Cmax) and area under the plasma drug concentration-time curve (AUC) were significantly greater after 27th than after 1st dosings in the ranitidine, but not in the nizatidine trials. The accumulation of ranitidine in plasma tended to be greater than that of nizatidine. Conclusion These results suggest that nizatidine is more safe for the repeated treatment in the very elderly patients. Clinical Pharmacology & Therapeutics (2004) 75, P10–P10; doi: 10.1016/j.clpt.2003.11.035

Lipophilicity affects the pharmacokinetics and toxicity of local anaesthetic agents administered by caudal block.

1. Drugs administered into the epidural space by caudal block are cleared by means of a process potentially affected by the lipophilic character of the compounds. 2. In the present study, we examined the relationship between the octanol-water partition coefficient (log Poct) and the time to reach the maximum plasma drug concentration (tmax) of lignocaine, bupivacaine and ropivacaine administered by caudal block in paediatric patients. We also examined the relationship between log Poct and the toxicity of these local anaesthetic agents in experimental models. The tmax and toxicity data were obtained from the literature. 3. Ropivacaine, with a log Poct of 2.9, exhibited a tmax of 61.6 min. The tmax of lignocaine, with a log Poct of 2.4, and bupivacaine, with a log Poct of with 3.4, were approximately 50% shorter than ropivacaine. At log Poct of approximately 3.0, the toxicity of these local anaesthetic agents was substantially increased. The relationship between log Poct and the convulsive effect in dogs was similar to the relationship between log Poct and the lethal dose in sheep. 4. With local anaesthetic agents, it appears that the relationship between log Poct and drug transfer from the epidural space to the blood stream is parabolic, being the slowest rate of transference at log Poct 3.0. Toxicity, due to plasma availability of these local anaesthetic agents, seems to be increased at log Poct equal or higher than 3.0 secondary to the highest transfer from plasma into the central nervous system.

Bioequivalence assessment of ambroxol tablet after a single oral dose administration to healthy male volunteers

A bioequivalence study of the ambroxol hydrochloride tablets was conducted. Twenty-four healthy male Korean volunteers received each medicine at the ambroxol hydrochloride dose of 30 mg in a 2×2 cross-over study. There was a 1-week washout period between the doses. Plasma concentrations of ambroxol were monitored by a high-performance liquid chromatography (HPLC) for over a period of 24 h after the administration. AUC t (the area under the plasma concentration–time curve from time 0 to last sampling time, 24 h) was calculated by the linear-log trapezoidal rule method. C max (maximum plasma drug concentration) and T max (time to reach C max) were compiled from the plasma concentration–time data. Analysis of variance was carried out using logarithmically transformed AUC t and C max, and untransformed T max. The geometric mean of AUC t was 495.8 ng ml −1 h −1 (test medication) and 468.3 ng ml −1 h −1 (reference medication). C max of 61.5 and 57.3 ng ml −1 were achieved for the test and the reference medication, respectively. The point estimates and 90% confidence intervals for AUC t (parametric) and C max (parametric) were, in point estimate (90% confidence interval), 1.058 (0.989–1.134) and 1.073 (1.007–1.142), respectively, satisfying the bioequivalence criteria of the European Committee for Proprietary Medicinal Products and the US Food and Drug Administration Guidelines. The corresponding value of T max was 0.229 (0.015–0.444). These results indicate that the two medications of ambroxol hydrochloride are bioequivalent and, thus, may be prescribed interchangeably.

뮤코펙트 정(염산암브록솔 30 mg)에 대한 암브렉트 정의 생물학적 동등성

A bioequivalence study of tablets (Dong Wha Pharm. Ind. Co., Ltd.) to tablets (Boehringer Ingelheim Korea, Ltd.) was conducted according to the guideline of Korea Food and Drug Administration (KFDA). Twenty four healthy male Korea volunteers received each medicine at the ambroxol hydrochloride dose of 30 mg in a crossover study. There was a one-week wash out period between the doses. Plasma concentrations of ambroxol were monitored by a high-performance liquid chromatography for over a period of 24 hours after the administration. (the area under the plasma concentration-time curve from time zero to 24 hr) was calulated by the linear trapezoidal rule method. (maximum plasma drug concentration) and were compiled from the plasma concentration-time data. Analysis of variance was carried out using logarithmically transformed . No significant sequence effect was found for all of the bioavailability parameters indicating that the crossover design was properly performed. The 90% confidence intervals of the ratio and the ratio for were 0.89-1.01 and 0.89-1.02, respectively. These values were within the acceptable bioequivalence intervals of 0.80-1.25. Thus, our study demonstrated the bioequivalence of with respect to the rate and extent of absorption.

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 (T max), 0.42 versus 0.75 hour; mean (SD) maximum plasma drug concentration (C max), 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 (AUC 0–∞), 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 C max, 105.08% to 137.59%; Ln-AUC 0–∞, 102.02% to 110.43%; and the difference in T max, −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 T max, C max, and C max/AUC parameters). This speed is especially important for a rapid analgesic or antipyretic effect.

Pharmacokinetics and pharmacodynamics of abarelix, a gonadotropin-releasing hormone antagonist, after subcutaneous continuous infusion in patients with prostate cancer.

Our objective was to evaluate the pharmacokinetic and pharmacodynamic characteristics of abarelix after continuous subcutaneous infusion of 50 microg x kg(-1) x d(-1) in patients with prostate cancer and to identify a plasma concentration of abarelix that may provide a sustained pharmacodynamic effect. This was a multicenter, open-label trial to evaluate abarelix, administered as a continuous subcutaneous infusion for up to 84 days (12 weeks) in 36 men with clinically localized or regional prostate cancer. All patients were treated at a dosage of 50 microg x kg(-1) x d(-1) for at least 28 days (4 weeks). The pharmacokinetic characteristics and the pharmacologic activities of abarelix on testosterone, prostate-specific antigen, dihydrotestosterone, follicle-stimulating hormone, and luteinizing hormone during and after treatment with abarelix were measured. After a continuous subcutaneous infusion of 50 microg x kg(-1) x d(-1), abarelix concentrations peaked with the median observed time to reach peak concentration at approximately 28 days. The mean observed maximum plasma drug concentration and average plasma concentration were 56.1 and 48.6 ng/mL, respectively. The mean observed half-life of abarelix was 10.0 days. Mean testosterone, dihydrotestosterone, follicle-stimulating hormone, and luteinizing hormone inhibition of 94.2%, 88.7%, 79.7%, and 82.8%, respectively, were achieved by study day 15 (14 days after dosing started), and inhibition continued to be maintained until the last dosing day. For the prostate-specific antigen levels, mean inhibition of 52.5% was achieved by 28 days after dosing started. The inhibition progressively increased and peaked at 81.9% on the final day of dosing. The inhibition for prostate-specific antigen was extended to 94.6% during the final follow-up visit (28 to 35 days after treatment ended). The median prostate gland volume reduction at treatment exit was 35%. The population pharmacodynamic estimates (percent coefficient of variation) of the 50% inhibitory concentration, maximum organ extraction ratio, and slope and sigmoidicity of the effect-concentration curve of abarelix to testosterone were 3.47 ng/mL (12.4%), 94.9 (1.3%), and 2.92 (16.2%), respectively. The results show that abarelix given as a subcutaneous infusion of 50 microg x kg(-1) x d(-1) is sufficient to produce clinically significant effects on the basis of prostate gland volume reduction and the suppression of gonadotropins.

Pilot study of hydrolytically activated paclitaxel prodrug therapy in patients with progressive malignancies

Background: The development of novel strategies based on chemotherapy with prodrugs is still a challenge for physicians developing effective treatment of malignancies in advanced-stage disease. In this study, we tested the hypothesis that this can be achieved by a prodrug of paclitaxel if the C7 hydroxyl group is blocked by condensation with a solketal chloroformate followed by a ring-opening reaction to the dihydroxyl derivative. Objective: The purpose of this study was to obtain information about toxicity, pharmacokinetic characteristics, and outcomes following paclitaxel prodrug therapy in 10 patients suffering from various progressive end-stage malignancies. Methods: Eligible patients had failed standard therapies and presented with progressive disease, were free of acute infections, had a total white blood cell count >2500 cells/mm 3 and platelet count of >150,000 cells/mm 3, and had not received chemo- or radiotherapy in the preceding 8 weeks. Subjects were treated with paclitaxel prodrug (pro Taxol) (100–1200 mg/m 2) under the compassionate-use Investigational New Drug setting, and toxicity was graded according to the National Cancer Institute's Common Toxicity Criteria (version 2.0). Pharmacokinetic characteristics of paclitaxel prodrug and paclitaxel released from the prodrug were determined by high-performance liquid chromatography. Results: Ten patients with different progressive malignancies were enrolled. Pharmacokinetic monitoring of treated patients demonstrated an increase in the serum half-life (∼5-fold, 14.0 hours vs 2.9 hours) and the maximum plasma drug concentration (∼50-fold, 110.0 μM vs 2.7 μM) of the paclitaxel prodrug over active paclitaxel, respectively. Furthermore, paclitaxel prodrug was shown to convert to active paclitaxel. The patients tolerated doses of ≤1200 mg/m 2, with transient liver toxicity starting at 450 mg/m 2. Grade 4 neutropenia was observed in 4 patients and required treatment with granulocyte colony-stimulating factor. Among the 10 enrolled patients, we observed 2 with complete remissions, 3 with partial responses, 1 with stable disease, and 4 with progressive disease. Conclusions: In this study, hydrolytically activated therapy with a paclitaxel prodrug resulted in decreased toxicity in patients based on a slow release of active paclitaxel. Encouraging effects on the course of the disease were observed, albeit in a heterogeneous patient population. These findings indicate that paclitaxel prodrug may further improve the success rate of chemotherapy with active paclitaxel.

Multiple-Dose Studies can be a More Sensitive Assessment for Bioequivalence than Single-Dose Studies : The Case with Omeprazole.

To evaluate the bioequivalence of two enteric-coated formulations of omeprazole, Losec® (reference) and Omepradex® (test). It is hypothesised that formulation differences may be accentuated following multiple-dose administration, and that testing after multiple administration may therefore provide a more sensitive assessment of bioequivalence. The study comprised two parts: an in vitro dissolution test and an in vivo bioavailability study. The latter was a randomised, two-way crossover comparative study after a single dose and after multiple doses in healthy volunteers. Forty subjects were randomly allocated to receive either test or reference product, once daily in the morning, and blood samples were taken on days 1 and 5. Standard pharmacokinetic analyses were performed, and analysis of variance (ANOVA) was used to compare the log-transformed variables in a model including terms for treatment, subject and period. Although both products meet the formal requirements specified by the United States Pharmacopoeia (USP) for enteric-coated articles, the in vitro dissolution experiments revealed widely differing properties for the two tested products. Less than 10% of the drug content was recovered from the Omepradex® formulation following a pre-exposure to pH 3 or 4, compared with over 90% recovered from the Losec® formulation. These findings were in agreement with the results of the in vivo bioavailability study, which showed that the two products differed in both their rate and extent of absorption after a single dose and following multiple doses. The products failed the bioequivalence test for area under the plasma concentration-time curve (AUC) and maximum plasma drug concentration (Cmax) after a single dose [AUC: test/reference ratio 0.85, 90% confidence interval (0.76-0.95); Cmax: test/reference ratio 0.85, 90% confidence interval (0.75-0.95)], and the difference between the formulations was even more pronounced after multiple doses [AUC: test/reference ratio 0.73, 90% confidence interval (0.65-0.83); Cmax: test/reference ratio 0.71, 90% confidence interval (0.63-0.81)]. These data suggest that bioequivalence studies on enteric-coated proton pump inhibitors should include both single- and multiple-dose elements to be fully decisive. The two omeprazole products failed to show bioequivalence, with the observed differences being even more apparent after multiple doses, as postulated. Based on this study, the two products may not be considered either therapeutically equivalent or interchangeable.

Effect of grapefruit juice on digoxin pharmacokinetics in humans

Grapefruit juice is responsible for drug interactions mediated by intestinal cytochrome P4503A4 inhibition and possibly P-glycoprotein inhibition in enterocytes. Our main objective was to determine whether grapefruit juice alters the bioavailability of digoxin, a P-glycoprotein substrate. The secondary objective was to determine whether the magnitude of the pharmacokinetic interaction was influenced by P-glycoprotein genetic polymorphism. Twelve healthy volunteers participated in this open randomized crossover study comparing the effect of grapefruit juice consumption (versus water) on the pharmacokinetics of a single oral dose of digoxin (0.5 mg). The P-glycoprotein genotype was determined according to MDR1 genetic polymorphism in exon 26 (C3435T). Grapefruit juice had no significant effect on the maximum plasma drug concentration (C(max)) of digoxin or the area under the plasma concentration-time curve (AUC) from time zero to 48 hours. However, there was a 9% increase in the digoxin AUC from time zero to 4 hours and from time zero to 24 hours (P =.01) during grapefruit juice administration. The digoxin renal clearance remained unchanged during both periods. No relationship between MDR1 C3435T genotype and early digoxin pharmacokinetic changes could be detected. The modest changes in digoxin pharmacokinetics observed during grapefruit juice ingestion do not support an important P-glycoprotein inhibition. Under our experimental conditions, grapefruit juice-mediated P-glycoprotein inhibition does not appear to play a relevant role in drug interactions, at least when assessed by use of digoxin disposition kinetics.

A population pharmacokinetic‐pharmacodynamic analysis and model validation of azimilide

Pharmacokinetic (PK) and pharmacodynamic (PD) models for azimilide were developed and validated with sparse blood sampling and QTc interval data obtained during three clinical trials of azimilide for prevention of supraventricular arrhythmia recurrence. Patients were orally administered placebo or azimilide dihydrochloride, 35, 50, 75, 100, or 125 mg/d, for 6 to 9 months. NONMEM was used for data fitting and assessment of selected patient covariates and concomitant medication classes for PK/PD relationships. Results indicate that azimilide clearance (CL) was dependent on body weight (WTKG), gender, and current tobacco use, where CL (L/h) = 3.92 x (WTKG - 43)(0.208), with a 17% increase for male subjects and a 15.5% increase for current tobacco use. Volume of distribution (V) was also dependent on WTKG and total bilirubin (BIL), where V (L) = 9.88 x (WTKG - 43) + 717 x (BIL)(0.348). The PK/PD analysis indicated that the baseline QTc interval was dependent on gender, New York Heart Association Class, digoxin, and paced artificial pacemaker spike, whereas the 50% effective concentration (EC(50)) was dependent on the serum potassium (K) level, where EC(50) = 107 x K. The change in EC(50) was not clinically significant within the normal range for potassium. The mean E(max) (maximum increase in the QTc interval for the E(max) models) was a 61.7 ms increase from baseline. At 125 mg/d the predicted percent increase in the QTc interval at the maximum plasma drug concentration at steady state was 9% and 10% for male and female patients, respectively. The values of the median prediction error were -3% and -0.4% for the PK and PK/PD models, respectively, and the values of the absolute prediction error were 21% and 4% for the PK and PK/PD models, respectively, indicating that both models are essentially unbiased and acceptably accurate. Azimilide PK parameters are dependent on body weight, gender, smoking status, and bilirubin and are independent of the coadministration of digoxin, warfarin, and cytochrome P4503A4 inhibitors and inducers. The relationship between azimilide concentration and change in QTc is primarily dependent on serum potassium.

A PHARMACOKINETIC AND PHARMACODYNAMIC COMPARISON OF DESMOPRESSIN ADMINISTERED AS WHOLE, CHEWED AND CRUSHED tablets, AND AS AN ORAL SOLUTION

We performed a crossover study to determine the relative pharmacokinetic bioavailability and antidiuretic activity of desmopressin in 16 orally hydrated, healthy human subjects. The investigation included 5 study periods with 1 period used to establish baseline diuresis in the absence of desmopressin and the remaining 4 randomized to a single 0.6 mg. oral dose of desmopressin administered as whole, crushed or chewed tablets, or as an oral solution. Serial plasma samples were collected for 12 hours for desmopressin pharmacokinetic analysis. Pharmacodynamics were assessed by measuring changes in urine volume and osmolality from baseline. Standard bioequivalence metrics were used to compare the pharmacokinetics and pharmacodynamics of crushed and chewed tablets, and oral solution to that of swallowing whole tablets. The 90% confidence interval analysis of log transformed plasma desmopressin area under the plasma concentration-time curve from time 0 to infinity and maximum plasma drug concentration showed that crushed and chewed tablet treatments were bioequivalent to swallowing whole tablets. The 90% confidence interval analysis for the decrease in urine volume and increase in urine osmolality demonstrated that crushed and chewed tablets, and oral solution treatments were equivalent to whole tablet treatment in the area under curve from time 0 to the last sampling time point and maximum drug effect. The results of this study imply that desmopressin administered orally as crushed or chewed tablets, or as an oral solution has the same net effect on decreasing urine volume and increasing urine osmolality as swallowing tablets whole.

Menstrual Cycle and Zidovudine Pharmacokinetics in HIV-Infected Women

To examine the pharmacokinetics of zidovudine during each menstrual cycle phase in women with HIV-1 infection. Open-label, nonblinded study. The immunodeficiency clinic at the Erie County Medical Center, Buffalo, New York. 12 HIV-seropositive women started and completed the study. Inclusion criteria for subjects included an acceptable medical history, chemistry profile, a complete blood count with differential, lymphocyte profile, urinalysis and history of regular menstrual cycles. All patients received a 100mg dose of zidovudine in a fasted state on three occasions. 8-hour pharmacokinetic profiles in the 12 women were obtained during the menstrual, follicular and luteal phases of the menstrual cycle. Serum estradiol, progesterone, cortisol and CD4+ and CD8+ cell counts were also obtained during each menstrual cycle phase. Considerable intra- and interpatient variability in zidovudine pharmacokinetics was evident. Plasma concentrations declined in a linear fashion over 4 hours following drug administration, with a prolonged elimination phase for most subjects. The overall mean elimination half-life of zidovudine was 1.6 ± 0.76h (range 0.56 to 3.7h) and the overall mean oral clearance was 2.32 ± 0.88 L/h/kg (range 1 to 4.7 L/h/kg). Time to maximum plasma drug concentration was 0.58 ± 0.27h, 0.77 ± 0.64h and 0.63 ± 0.29h during the menstrual, follicular and luteal phases, respectively (p = 0.555). The mean peak plasma concentration of zidovudine was 684 ± 502 μg/L, 666 ± 562 μg/L and 527 ± 210 μg/L during the three phases, respectively (p = 0.472). The mean zidovudine area under the concentration-time curve (AUC) during the studied phases was 781 ± 279 μg h/L, 875 ± 391 μg h/L and 693 ± 176 μg h/L, respectively (p = 0.128). The AUC was negatively correlated with estradiol serum concentration (r = −0.329, p < 0.05). Conclusion: There were no significant differences in the zidovudine pharmacokinetic parameters across the menstrual cycle phases, but there was high inter-subject variability during each cycle phase. A significant negative relationship was found between zidovudine AUC and estradiol concentrations, suggesting that zidovudine glucuronidation may change in relation to the menstrual cycle phase. Hormonal variation and fluctuations in women, especially estrogen, may therefore explain in part the unpredictability of zidovudine exposure after an oral dose. This may impact plasma concentrations of zidovudine and potentially cause fluctuating concentrations throughout prolonged periods each month.

The effect of in vivo dissolution, gastric emptying rate, and intestinal transit time on the peak concentration and area-under-the-curve of drugs with different gastrointestinal permeabilities.

To theoretically investigate the impact of gastric emptying half-time, intestinal transit time and the time for 85% in vivo dissolution on the peak concentration and area-under-the curve of model drugs. Simulations were performed using mathematical models of gastrointestinal physiology and pharmacokinetics of model drugs with different gastrointestinal permeability. They were used to investigate the effect of different permutations of gastric emptying times, intestinal transit times, dissolution rates and effective permeabilities on the maximum plasma drug concentration and the area-under-the-curve of immediate release tablets relative to an oral solution (i.e., Cmax(tablet)/Cmax(solution) and AUC(tablet)/AUC(solution)). The higher the permeability of the drug, the more sensitive the Cmax ratio is to dissolution rate and gastric emptying rate. As the intestinal transit time becomes more rapid, the sensitivity to T85% dissolution time and gastric emptying half-time increases. There is less dependence for the AUC ratio on the gastric emptying time and dissolution rate. Under the assumptions of the models, the criterion of 85% dissolution in 15 minutes (T85%) for classifying a rapidly dissolving drug product is relatively conservative since the Cmax ratio exceeded 0.8 for a T85% dissolution time of one hour and a gastric emptying half-time faster than 0.2 hour over a wide range of permeabilities.

Application of a combined "effect compartment/indirect response model" to the central nervous system effects of tiagabine in the rat.

Pharmacological inhibition of GABA uptake transporters provides a mechanism for increasing GABAergic transmission, which may be useful in the treatment of various neurological disorders. The purpose of our investigations was to develop an integrated pharmacokinetic-pharmacodynamic (PK/PD) model for the characterization of the pharmacological effect of tiagabine, R-N-(4,4-di-(3-methylthien-2-yl)but-3-enyl)nipecotic acid, in individual rats in vivo. The tiagabine-induced increase in the amplitude of the EEG 11.5-30 Hz frequency band (beta), was used as pharmacodynamic endpoint. Chronically instrumented male Wistar rats were randomly allocated to four groups which received an infusion of 3, 10, or 30 mg kg-1 of tiagabine or vehicle over 10 min. The EEG was continuously recorded in conjunction with frequent arterial blood sampling. The pharmacokinetics of tiagabine could be described by a biexponential equation. The pharmacokinetics of tiagabine were not dose dependent, and the pooled values for clearance, volume of distribution at steady state and terminal half-life were (mean +/- SE, n 23) 96 +/- 9 ml min-1 kg-1, 1.5 +/- 0.1 L kg-1 and 20 +/- 0.2 min. A time delay was observed between the occurrence of maximum plasma drug concentrations and maximal response. A physiological PK/PD model has been used to account for this time delay, in which a biophase was postulated to account for tiagabine available to the GABA uptake carriers in the synaptic cleft and the increase in EEG effect was considered an indirect response due to inhibition of GABA uptake carriers. The population values for the pharmacodynamic parameters characterizing the delay in pharmacological response relative to plasma concentrations were keo = 0.030 min-1 and kout = 81 min-1, respectively. Because of the large difference in these values the PK/PD model was simplified to the effect compartment model. Population estimates (mean +/- SE) were E0 = 155 +/- 6 microV, Emax = 100 +/- 5 microV, EC50 = 287 +/- 7 ng ml-1, Hill factor = 1.8 +/- 0.2 and keo = 0.030 +/- 0.002 min-1. The results of this analysis show that for tiagabine the combined "effect compartment-indirect response" model can be simplified to the classical "effect compartment" model.

Pharmacokinetics of Oral Artesunate in Thai Patients with Uncomplicated Falciparum Malaria

The pharmacokinetics of artesunate and its major plasma metabolite, dihydroartemisinin, were investigated in 11 Thai male patients with acute uncomplicated falciparum malaria during the acute and recovery phases. Patients were given an oral dose of 200mg artesunate (Guilin Pharmaceutical) on the first day, followed by 100mg 12 hours later, then 100mg daily for another 4 days (total dose of 700mg). All the patients showed a rapid initial response with median (range) parasite and fever clearance times of 30 (18 to 60) and 24 (4 to 94) hours, respectively; no patients showed reappearance of parasites during the 28-day follow-up period. No significant clinical adverse effects were detected in any patient. Acute phase malaria infection significantly influenced the pharmacokinetics of artesunate and its active metabolite, dihydroartemisinin. Maximum plasma drug concentration (C(max)), absorption half-life (t((1/2)a)), area under the plasma concentration-time curve from zero to the last observed time (AUC) and terminal elimination half-life (t((1/2)z)) of artesunate were decreased, while apparent total body clearance (CL/f) was increased during the acute phase, compared with the recovery phase. In addition, a decrease in the C(max) and an increase in the AUC(DHA/ARS ) ratio were found. Optimisation of therapy with oral artesunate should therefore be based on the kinetics of the drug and dihydroartemisinin in malaria patients with acute phase infection.

Comparative Bioavailability Study of Two Oral Omeprazole Formulations after Single and Repeated Administrations in Healthy Volunteers

Two oral enteric-coated pellet formulations of omeprazole, Pepticum((R)) (test formulation) and Mopral((R)) (reference), were administered to 24 healthy volunteers for 5 days at a daily dose of 20mg omeprazole in order to investigate the comparative bioavailability of the two formulations. The data obtained in this study demonstrated the bioequivalence of the two formulations. No statistical differences were observed for the area under the plasma concentration-time curve (AUC(0-t)), the parameter to which the inhibition of acid secretion induced by omeprazole is directly related. Differences observed in maximum plasma drug concentration (C(max)) at day 1 for both formulations were not statistically significant. At steady-state, the differences found in C(max) were associated with a p-value <0.05 with the 90% confidence interval lying between the acceptance range (70 to 140%). Regarding time to reach C(max) (t(max)), p < 0.01 was found both after single and repeated doses. In both cases, Pepticum((R)) showed a delay in reaching C(max) compared with Mopral((R)): 2.15 +/- 1.11 vs 1.48 +/- 0.52h (day 1) and 1.94 +/- 0.66 vs 1.31 +/- 0.75h (day 5). This study confirmed the reported increases in AUC and C(max) after repeated administrations, the important intersubject variability and the excellent biological and clinical tolerability of both formulations.

Drug interactions with grapefruit juice. Extent, probable mechanism and clinical relevance.

Concomitant intake with grapefruit juice increases the concentrations of many drugs in humans. The effect seems to be mediated mainly by suppression of the cytochrome P450 enzyme CYP3A4 in the small intestine wall. This results in a diminished first pass metabolism with higher bioavailability and increased maximal plasma concentrations of substrates of this enzyme. The effect was most pronounced in drugs with a high first pass degradation and in many cases has the clear potential to reach clinical relevance, as shown by an occasional change in drug effects or tolerability. For felodipine, nitrendipine, nisoldipine and saquinavir, the interaction was most marked with median increases of area under the curve (AUC) and/or the maximum (peak) plasma drug concentration after single-dose administration (Cmax) values exceeding 70% of respective control periods. Less pronounced, but possibly relevant, concentration increases were found for nifedipine, nimodipine, verapamil, cyclosporin, midazolam, triazolam and terfenadine. This list is not complete because many drugs have not been studied yet. The components of grapefruit juice which are the most probable causes of the interactions are psoralen derivatives, but the flavonoid naringenin may also contribute. Concomitant grapefruit juice intake does not generally decrease the variability of drug pharmacokinetic parameters. Therefore, it is recommended that patients refrain from drinking grapefruit juice when they are taking a drug that is extensively metabolised, unless a lack of interaction has already been demonstrated for the drug. It is also recommended that drugs possibly interacting with grapefruit juice should be appropriately labelled. A place for grapefruit juice as a drug-sparing agent in treatment involving expensive medicine cannot be derived from the information currently available on grapefruit juice interactions.

A New Rapidly Disintegrating Formulation of Cisapride is Bioequivalent to Standard Cisapride Tablets in the Elderly

Thirty-six healthy, elderly subjects were enrolled in an open-label, randomised, crossover study to determine the relative bioavailability of a new, rapidly disintegrating formulation of cisapride (Propulsid® Quicksolv®) compared with the currently marketed cisapride preparation (Propulsid®). Subjects received a single 10mg dose of each formulation, separated by a 1-week washout period. Blood samples for determination of cisapride concentrations were taken regularly until 48 hours after drug administration. After ingestion of Propulsid Quicksolv, the log-transformed least square means value for area under the plasma concentration-time curve up to the last measurable time-point (AUClast) was 444.9 µg/L·h, AUC extrapolated to infinity (AUC∞) was 488.8 µ,g/L·h, and maximum plasma drug concentration (Cmax) was 43.3 µg/L. After ingestion of Propulsid®, the corresponding values were 449.1 µg/L·h, 513.7 µg/L·h, and 43.9 µg/L, respectively. The limits of the 90% confidence intervals for these log-transformed parameters were all within the range set to declare bioequivalence (80 to 125%). Mild to moderately severe gastrointestinal symptoms occurred in one subject after administration of Propulsid® Quicksolv®. Neither formulation was orally irritating, and no clinically significant changes in vital signs, ECGs or laboratory test parameters were noted. The 10mg Propulsid® Quicksolv® tablet was bioequivalent to the marketed Propulsid® tablet in healthy, elderly subjects and was also a convenient, well-tolerated alternative to the Propulsid® tablet.

Clinical Pharmacokinetics of Articaine

Articaine is the most widely used local anaesthetic agent in dentistry in a number of European countries. The amide structure of articaine is similar to that of other local anaesthetics, but it contains an additional ester group which is quickly hydrolysed by esterases. High performance liquid chromatography has been used to determine the concentrations of articaine and its metabolite articainic acid in serum. Rapid sample preparation is critical in the accurate determination of articaine serum concentrations, since blood and serum are the sites of metabolism. The time to maximum drug concentrations of articaine occurs about 10 to 15 minutes after submucosal injection of articaine 4% 80 mg, irrespective of epinephrine (adrenaline). The mean maximum plasma drug concentration is about 400 micrograms/L for articaine with epinephrine 1:200,000 and 580 micrograms/L for articaine without epinephrine. The elimination half-time of articaine is about 20 minutes. The rapid breakdown of articaine to the inactive metabolite articainic acid is related to a very low systemic toxicity and consequently to the possibility of repeated injections. Equal analgesic efficacy along with lower systemic toxicity (i.e. a wide therapeutic range) permits the use of articaine in higher concentrations than other amide-type local anaesthetics. Complete anaesthesia can be observed in nearly 90% of all cases, using articaine 4% 60 to 80 mg with epinephrine 1:200,000. Articaine is better able to diffuse through soft tissue and bone than other local anaesthetics. The concentration of articaine in the alveolus of a tooth in the upper jaw after extraction was about 100 times higher than that in systemic circulation. The plasma protein binding rate of articaine and articainic acid is 70%. It has been concluded that an unintentional intravascular injection of articaine 80 mg does not cause toxic effects in healthy individuals.