Pharmacokinetic and pharmacodynamic profile of linezolid in healthy volunteers and patients with Gram-positive infections

The pharmacokinetics and pharmacodynamics of linezolid have been extensively investigated in laboratory models, healthy volunteers and patients. Three formulations exist: an intravenous (iv) form, film-coated tablets and an oral suspension. Linezolid can be assayed in serum and body fluids by HPLC and has good bioavailability with a Cmax at 0.5-2 h. The protein binding is 31%, and the volume of distribution is 30-50 L with adequate to good tissue penetration into skin blister fluids, bone, muscle, fat, alveolar cells, lung extracellular lining fluid and CSF. There are two major metabolites of linezolid (PNU-142586 and PNU-142300). Non-enzymic formation of PNU-142586 is the rate-limiting step in the clearance of linezolid, and linezolid and its two main metabolites plus several minor ones are all excreted in the urine. Dose linearity is evident in the Cmax and AUC across a wide range of doses. Gender and age have little effect on pharmacokinetics, but children have greater plasma clearance and volume of distribution and hence, have lower serum concentrations for equivalent doses in adults. No dose modification is needed in mild to moderate liver disease or any degree of renal impairment; however, both PNU-142586 and PNU-142300 accumulate in renal failure. Linezolid is bacteriostatic with a significant post-antibiotic effect against the key pathogens. In animal models of infection, the time the antibiotic concentration exceeds the MIC (t > MIC) helps to determine outcome, and a t > MIC of 40% is predictive of a bacteriostatic effect for both staphylococci and pneumococci. In man, t > MIC and AUC/MIC have been related to bacteriological and clinical outcomes. AUC and length of treatment are also related to the risk of thrombocytopenia.     

Pharmacokinetic interaction between ketoconazole and praziquantel in healthy volunteers

BACKGROUND: Praziquantel, a broad-spectrum anthelminthic, has been reported to undergo extensive first-pass metabolism by cytochrome P450 (CYP) enzymes in vivo. Ketoconazole, a potent CYP3A4 inhibitor, is known to markedly increase plasma concentrations of many co-administered drugs. However, no data are available on the potential pharmacokinetic drug interaction between ketoconazole and praziquantel in humans. OBJECTIVE: To investigate the potential pharmacokinetic interaction of ketoconazole with praziquantel in healthy adult Thai male volunteers. METHODS: In an open-label, randomized two-phase crossover study, separated by a 2-week period, 10 healthy adult Thai male volunteers ingested a single dose of 20 mg/kg praziquantel alone or with co-administration of 400-mg ketoconazole orally daily for 5 days. Venous blood samples were collected at specific times for a 24-h period. Plasma concentrations of praziquantel were determined using high-performance liquid chromatography. A non-compartmental model was applied for pharmacokinetic parameter analysis of praziquantel. RESULTS: Concurrent administration of ketoconazole with praziquantel significantly increased the mean area under the curve from time zero to infinity (AUC(0-alpha)) and maximum plasma concentration (Cmax) of praziquantel by 93% (955.94 +/- 307.74 vs. 1843.10 +/- 336.39 ng h/mL; P < 0.01) and 102% (183.38 +/- 43.90 vs. 371.31 +/- 44.63 ng/mL; P < 0.01), respectively, whereas the mean total clearance (Cl/F) of praziquantel was significantly decreased by 58% (2.65 +/- 0.64 vs. 1.11 +/- 0.35 mL/h/kg; P < 0.01). CONCLUSION: Ketoconazole co-administration alters the pharmacokinetics of praziquantel in humans, possibly through inhibition of CYP3A, particularly CYP3A4, first-pass metabolism of praziquantel. Our data suggest that when praziquantel is co-administered with ketoconazole, the dose of praziquantel could be reduced to half the standard dose of praziquantel to reduce the cost of therapy.     

Pharmacokinetic interaction between verapamil and almotriptan in healthy volunteers

OBJECTIVE: To assess the interaction between almotriptan, a 5-HT1B/1D-receptor agonist used to treat migraine, and verapamil, an agent for migraine prophylaxis. METHODS: Twelve healthy volunteers received the following treatments in a crossover design: (1) 120-mg sustained-release verapamil tablet twice daily for 7 days and one 12.5-mg almotriptan tablet on day 7 and (2) one 12.5-mg almotriptan tablet alone on day 7. Serial plasma and urine samples were obtained on day 7. Almotriptan plasma concentrations were determined by liquid chromatography-tandem mass spectrometry; urine samples were analyzed by ultraviolet HPLC. Safety measures included blood pressure and pulse measurements, electrocardiography, and adverse event monitoring. Statistical comparisons of pharmacokinetic parameters and vital sign data were made by ANOVA. RESULTS: Mean almotriptan peak concentration and area under the plasma concentration-time curve were significantly higher and volume of distribution and oral clearance were significantly lower after coadministration of almotriptan and verapamil compared with administration of almotriptan alone. The magnitudes of these differences were approximately 20%. Renal clearance was unaffected by verapamil coadministration. No significant effects of treatment on blood pressure or pulse were detected, with the exception of sitting systolic blood pressure at 2 hours after administration. However, the difference in mean change from baseline at this time point was only 8 mm Hg. CONCLUSIONS: Verapamil modestly inhibited almotriptan clearance to a degree consistent with the modest contribution of CYP3A4 to almotriptan metabolism. This observation and the lack of effect of verapamil on the tolerability to almotriptan administration suggest that no reduction of the almotriptan dose is warranted.     

Pharmacokinetic interaction between ivabradine and carbamazepine in healthy volunteers

What is known and Objective: Ivabradine is a novel heart rate‐lowering agent that selectively and specifically inhibits the depolarizing cardiac pacemaker If current in the sinus node. Our objective was to evaluate a possible pharmacokinetic interaction between ivabradine and carbamazepine in healthy volunteers. Methods: The study consisted of two periods: Period 1 (Reference), when each volunteer received a single dose of 10 mg ivabradine and Period 2 (Test), when each volunteer received a single dose of 10 mg ivabradine and 400 mg carbamazepine. Between the two periods, the subjects were treated for 15 days with a single daily dose of 400 mg carbamazepine. Plasma concentrations of ivabradine were determined during a 12‐h period following drug administration, using a high‐throughput liquid chromatography with mass spectrometry analytical method. Pharmacokinetic parameters of ivabradine administered in each treatment period were calculated using non‐compartmental and compartmental analysis to determine if there were statistically significant differences. Results and Discussion: In the two periods of treatments, the mean peak plasma concentrations (C_max) were 16·25 ng/mL (ivabradine alone) and 3·69 ng/mL (ivabradine after pretreatment with carbamazepine). The time taken to reach C_max, t_max, were 0·97 and 1·14 h, respectively, and the total areas under the curve (AUC_0‐∞) were 52·49 and 10·33 ng h/mL, respectively. These differences were statistically significant for C_max and AUC_0‐∞ when ivabradine was administered with carbamazepine, whereas they were not for t_max, half‐life and mean residence time. What is new and Conclusion: TCarbamazepine interacts with ivabradine in healthy volunteers, and lowers its bioavailability by about 80%. This magnitude of effect is likley to be clinically significant.     

Pharmacokinetic interaction between amprenavir and clarithromycin in healthy male volunteers

The P450 enzyme, CYP3A4, extensively metabolizes both amprenavir and clarithromycin. To determine if an interaction exists when these two drugs are coadministered, the pharmacokinetics of amprenavir and clarithromycin were investigated in healthy adult male volunteers. This was a Phase I, open-label, randomized, balanced, multiple-dose, three-period crossover study. Fourteen subjects received the following three regimens: amprenavir, 1,200 mg twice daily over 4 days (seven doses); clarithromycin, 500 mg twice daily over 4 days (seven doses); and the combination of the above regimens over 4 days (seven doses of each drug). Twelve subjects completed all treatments and the follow-up period. The erythromycin breath test (ERMBT) was administered at baseline, 2 h after the final dose of each of the three regimens and at the first follow-up visit. Coadministration of clarithromycin and amprenavir significantly increased the mean amprenavir AUC(ss), C(max,ss), and C(min,ss) by 18, 15, and 39%, respectively. Amprenavir had no significant effect on the AUC(ss) of clarithromycin, but the median T(max,ss)for clarithromycin increased by 2.0 h, renal clearance increased by 34%, and the AUC(ss) for 14-(R)-hydroxyclarithromycin decreased by 35% when it was given with amprenavir. Amprenavir and clarithromycin reduced the ERMBT result by 85 and 67%, respectively, and by 87% when the two drugs were coadministered. The baseline ERMBT value did not correlate with clearance of amprenavir or clarithromycin. A pharmacokinetic interaction occurs when amprenavir and clarithromycin are coadministered, but the effects are not likely to be clinically important, and coadministration does not require a dosage adjustment for either drug.     

Pharmacokinetic interaction between intravenous phenytoin and amiodarone in healthy volunteers

To determine the mechanism of the amiodarone-phenytoin interaction, seven healthy male subjects were given intravenous phenytoin, 5 mg/kg, before (phase I) and after (phase II) 3 weeks of oral amiodarone, 200 mg/day. Serum AUC increased from 245 +/- 37.6 to 342 +/- 87.3 mg.hr/L (p = 0.007); area under the first moment curve increased from 5666 +/- 1003 to 11,632 +/- 4198 mg.hr2/L (p = 0.008); the time-averaged total body clearance decreased from 1.57 +/- 0.3 to 1.17 +/- 0.33 L/hr (p = 0.0004); and the apparent elimination half-life increased from 16.1 +/- 1.32 to 22.6 +/- 3.8 hours (p = 0.001) for phenytoin during phase II. The volume of distribution at steady state and the unbound fraction for phenytoin remained unchanged. However, the formation of p-hydroxyphenytoin as a function of serum phenytoin concentration decreased during phase II. These findings suggest that amiodarone inhibits phenytoin metabolism. These observations also suggest that phenytoin doses will need to be reduced when coadministered with amiodarone. The magnitude of this reduction is difficult to predict because of the saturable pharmacokinetics of phenytoin, and therapeutic monitoring is recommended if amiodarone is added to the phenytoin regimen.     

Pharmacokinetic and pharmacodynamic interactions between diltiazem and methylprednisolone in healthy volunteers

OBJECTIVES: The pharmacokinetics and pharmacodynamics after administration of methylprednisolone alone, diltiazem alone, and both drugs jointly were assessed in healthy volunteers. METHODS: An unblinded, controlled, fixed-sequence, 2-period study was carried out in 5 healthy white men who received a single dose of intravenous methylprednisolone, 0.3 mg/kg, on day 2, followed by diltiazem alone, 180 mg, on days 5, 6, and 7, with joint dosing of both drugs on day 8. Methylprednisolone and diltiazem disposition was assessed from plasma concentrations. Pharmacodynamic factors were assessed by plasma cortisol and T-helper and T-suppressor lymphocytes by means of extended indirect response models. RESULTS: The clearance of methylprednisolone was significantly reduced in the presence of diltiazem (25.2 L/h versus 16.8 L/h), resulting in a longer half-life (2.28 hours versus 3.12 hours) and increased area under the plasma concentration-time curve (AUC) (871 ng x h/mL versus 1299 ng x h/mL). The AUC of diltiazem was unchanged in the presence of methylprednisolone. No significant intrinsic pharmacodynamic differences were observed for methylprednisolone versus methylprednisolone-diltiazem. The 50% inhibitory concentration values were 0.446 ng/mL versus 0.780 ng/mL for cortisol, 9.20 ng/mL versus 10.7 ng/mL for T-helper cells, and 18.5 ng/mL versus 20.9 ng/mL for T-suppressor cells (P >.05). Greater net suppression, as indicated by the area between the effect curve and suppression ratios, was observed for the methylprednisolone-diltiazem combination versus methylprednisolone alone, which was attributed to reduced elimination of methylprednisolone. CONCLUSIONS: Controlled-delivery diltiazem, 180 mg, significantly increased methylprednisolone AUC and half-life and reduced clearance, lending to greater systemic exposure to the steroid. However, significant differences between 50% inhibitory concentration values for methylprednisolone when given alone and for methylprednisolone in combination with diltiazem were not seen, which implies no change in cortisol or cell-trafficking sensitivity in the presence of diltiazem.     

Multiple-dose pharmacokinetics and tolerability of gemifloxacin administered orally to healthy volunteers

Gemifloxacin mesylate (SB-265805-S, LB-20304a) is a potent, novel fluoroquinolone agent with a broad spectrum of antibacterial activity. The pharmacokinetics and tolerability of oral gemifloxacin were characterized in two parallel group studies in healthy male volunteers after doses of 160, 320, 480, and 640 mg once daily for 7 days. Multiple serum or plasma and urine samples were collected on days 1 and 7 and were analyzed for gemifloxacin by high-performance liquid chromatography (HPLC)-fluorescence (study 1) or HPLC-mass spectrometry (study 2). Safety assessments included vital signs, 12-lead electrocardiogram (ECG) readings, hematology, clinical chemistry, urinalysis, and adverse experience monitoring. Gemifloxacin was rapidly absorbed, with a time to maximum concentration of approximately 1 h after dosing followed by a biexponential decline in concentration. Generally, maximum concentration and area under the concentration-time curve (AUC) increased linearly with dose after either single or repeat doses. Mean +/- standard deviation values of AUC(0-tau) on day 7 were 4.92 +/- 1.08, 9.06 +/- 2.20, 12.2 +/- 3.69, and 20.1 +/- 3.67 microg x h/ml following 160-, 320-, 480-, and 640-mg doses, respectively. The terminal-phase half-life was approximately 7 to 8 h, independent of dose, and was similar following single and repeated administrations. There was minimal accumulation of gemifloxacin after multiple dosing. Approximately 20 to 30% of the administered dose was excreted unchanged in the urine. The renal clearance was 160 ml/min on average after single and multiple doses, which was slightly greater than the accepted glomerular filtration rate (approximately 120 ml/min). These data show that the pharmacokinetics of gemifloxacin are linear and independent of dose. Gemifloxacin was generally well tolerated, although one subject was withdrawn from the study after 6 days at 640 mg for mild, transient elevations of alanine aminotransferase and aspartate aminotransferase not associated with any clinical signs or symptoms. There were no other significant changes in clinical chemistry, hematology or urinalysis parameters, vital signs, or ECG readings. In conclusion, the results of these studies, combined with the antibacterial spectrum and potency, support the further investigation of once-daily administration of gemifloxacin for indications such as respiratory tract and urinary tract infections.     

Pharmacokinetic modeling of plasma and intracellular concentrations of raltegravir in healthy volunteers

Raltegravir is a potent inhibitor of HIV integrase. Persistently high intracellular concentrations of raltegravir may explain sustained efficacy despite high pharmacokinetic variability. We performed a pharmacokinetic study of healthy volunteers. Paired blood samples for plasma and peripheral blood mononuclear cells (PBMCs) were collected predose and 4, 8, 12, 24, and 48 h after a single 400-mg dose of raltegravir. Samples of plasma only were collected more frequently. Raltegravir concentrations were determined using liquid chromatography-mass spectrometry. The lower limits of quantitation for plasma and PBMC lysate raltegravir were 2 nmol/liter and 0.225 nmol/liter, respectively. Noncompartmental analyses were performed using WinNonLin. Population pharmacokinetic analysis was performed using NONMEM. Six male subjects were included in the study; their median weight was 67.4 kg, and their median age was 33.5 years. The geometric mean (GM) (95% confidence interval shown in parentheses) maximum concentration of drug (C(max)), area under the concentration-time curve from 0 to 12 h (AUC(0-12)), and area under the concentration-time curve from 0 h to infinity (AUC(0-∞)) for raltegravir in plasma were 2,246 (1,175 to 4,294) nM, 10,776 (5,770 to 20,126) nM · h, and 13,119 (7,235 to 23,788) nM · h, respectively. The apparent plasma raltegravir half-life was 7.8 (5.5 to 11.3) h. GM intracellular raltegravir C(max), AUC(0-12), and AUC(0-∞) were 383 (114 to 1,281) nM, 2,073 (683 to 6,290) nM · h, and 2,435 (808 to 7,337) nM · h (95% confidence interval shown in parentheses). The apparent intracellular raltegravir half-life was 4.5 (3.3 to 6.0) h. Intracellular/plasma ratios were stable for each patient without significant time-related trends over 48 h. Population pharmacokinetic modeling yielded an intracellular-to-plasma partitioning ratio of 11.2% with a relative standard error of 35%. The results suggest that there is no intracellular accumulation or persistence of raltegravir in PBMCs.     

Pharmacokinetic comparison of oral and local action transcutaneous flurbiprofen in healthy volunteers

Flurbiprofen is a propionic acid–derived nonsteroidal anti–inflammatory drug (NSAID) used widely in the treatment of rheumatism and nonarthritic pain. The pharmacokinetics of topically and orally administered flurbiprofen were compared in a two–part, open study involving healthy adult volunteers. In the first (cross–over) part of the study, 12 Caucasians were randomized to receive either a single oral dose of 50 mg flurbiprofen or a single topical application of a novel 40 mg flurbiprofen–containing patch on the right wrist for 12 h. In the second part of the study, each subject applied a flurbiprofen–containing patch twice daily to the same wrist for 7 days. Plasma concentrations of flurbiprofen and urinary concentrations of the NSAID and its metabolites were measured by high–performance liquid chromatography assay, to enable comparison of the pharmacokinetic parameters for delivery of the drug by both routes. Maximum concentrations of the NSAID in plasma (C_max) were much lower after a single application of the topical 40 mg flurbiprofen patch than after a single oral dose of 50 mg of the NSAID (mean ± SD: 43 ± 16 ng/ml versus 5999 ± 1300 ng/ml, respectively). After repeated application of the topical patch, C_max increased only slightly to 103 ± 57 ng/ml. The mean relative bioavailability of flurbiprofen from the patch was 3–5 ± 1–7%, calculated from plasma area under the curve data and 4-4 ± 2–8% from urinary excretion data. The temporal profile of the appearance of flurbiprofen in the circulation also differed, with maximum concentrations occurring (T_max) 2 ± 1 h after the oral dose but not until 20 ± 6 h of applying the first patch, decreasing to 4 ± 3 h after repeated applications. Steady–state plasma concentrations were reached within 5 days of repeated patch applications; these exhibited intersubject variability ranging from 32 to 285 ng/ml. Percutaneous absorption of flurbiprofen from the patch into the systemic circulation was thus relatively slow and systemic concentrations of the drug achieved by this route were much lower than those obtained after oral intake of comparable doses. The systemic concentrations achieved via the topical route are likely to be insufficient to account for the demonstrable efficacy of the formulation in clinical trials, which is considered to depend on local enhanced topical delivery of flurbiprofen. Moreover, it might reasonably be supposed that the use of the flurbiprofen–containing patch as a localized treatment for musculoskeletal soft–tissue lesions will elicit a lower incidence of systemic adverse effects than occurs with the orally administered NSAID.     

Pharmacokinetic profile of talipexole in healthy volunteers is not altered when it is co-administered with Madopar (co-beneldopa)

Objectives:  To investigate the pharmacokinetics of talipexole hydrochloride tablets and the potential influence of Madopar (benserazide and levodopa combination; co-beneldopa) tablets on talipexole's pharmacokinetics when the two tablets are co-administered orally to healthy Chinese volunteers.
Methods:  A sensitive liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed to measure talipexole concentration in human plasma in an open-label, randomized, two-way crossover, single-dose study, with 1-week washout period. Healthy Chinese volunteers were randomized to receive talipexole tablets either alone or together with Madopar tablets by oral administration after an overnight fast. Serial blood samples were collected for a period of 36 h after the administration. Pharmacokinetic parameters C _max, t _max, t _{1/2 z} , mean residence time (MRT), AUC_0−τ, AUC_0−∞, CL _z / F and V _z / F were determined under the non-compartmental model. Pharmacokinetic values of talipexole administered alone to the subjects were compared with those administered simultaneously with Madopar to determine whether or not the differences were statistically significant.
Results:  The subjects experienced mild gastrointestinal irritation when talipexole was administered alone as well as together with Madopar. For talipexole hydrochloride, there were no significant differences in the pharmacokinetic values between the two administrations. No pharmacokinetic differences based on gender were observed either.
Conclusion:  A single oral dose of Madopar co-administered with talipexole does not significantly change talipexole's pharmacokinetics in human.     

Electrocardiographic profile of oral piperazine citrate in healthy volunteers

The electrocardiographic (ECG) profile of oral piperazine citrate was determined in healthy volunteers. Piperazine caused reduction in heart rate in all the subjects. The highest percentage of change was 15.7. The average pretreatment (73.6+/-6.59 beats/min) when compared with the heart rate 1 hour after piperazine was administered (64.6+/-5.21 beats/min) was statistically significant (P=0.0054). The QT and JT intervals had average increases of 9.7% and 11.1%, respectively. In contrast, piperazine did not have any effect on the QRS complex following its administration. However, the average PR interval 1 hour after ingesting oral piperazine 2 g was significantly prolonged, 0.18+/-0.0063 seconds compared with a pretreatment average of 0.16+/-0.0098 seconds. The difference between the 2 values was statistically significant (P=0.0161). No dysrhythmic phenomena were seen. Sinus rhythm was maintained in all the volunteers, with every QRS-T complex preceded by a P wave. The direction and magnitude of the mean electric axis of QRS complex and T wave were not altered by piperazine. It is concluded that oral piperazine citrate induced some changes on the ECG profile of healthy human volunteers, typical of many potent antiarrhythmic agents.     

Pharmacokinetics and tolerability of teicoplanin in healthy volunteers after single increasing doses.

In this double-blind, randomized study, five healthy subjects per group received doses of 15, 20, or 25 mg of teicoplanin per kg of body weight, and one subject per group received a 0.9% NaCl placebo as single intravenous infusion over 30 min. Serial blood samples and urine were collected for 13 days postadministration, and concentrations of teicoplanin were determined by microbiological assay. The pharmacokinetic data were analyzed by noncompartmental and compartmental analyses. Laboratory safety tests, audiometry, and serum creatinine clearance measurements were done prior to day 1 and on days 2 and 14. In the three groups, peak levels at the end of the infusion averaged 194, 197, and 253 mg/liter, respectively. Mean concentrations in plasma 24 h after the administration were 10.5, 13.6, and 19.8 mg/liter, respectively. Mean values of volume of distribution at steady state were 0.80, 0.87, and 0.87 liters/kg, respectively. Terminal half-lives averaged 88, 83, and 92 h. Mean total clearance values were 10.9, 11.0, and 11.3 mg/h/kg, respectively, with renal clearance accounting for 75, 81, and 78%, respectively, of the total. The 13-day cumulative mean urinary recovery ranged from 71 to 78% of the dose within the groups. The pharmacokinetics of teicoplanin appears to be linear in the range of administered doses. Teicoplanin was generally well tolerated. Side effects, appearing in five subjects, were represented by fevers, chills, and skin reactions; these adverse reactions were mild, but one episode of rash necessitated the interruption of infusion, and one episode of chills necessitated treatment with corticosteroids. There was no indication of drug-related modifications of laboratory test results.     

Pharmacokinetic interaction between TMC114/r and efavirenz in healthy volunteers

BACKGROUND: This open-label, crossover study investigated the pharmacokinetic interaction between TMC114 (darunavir [Prezista]), administered with low-dose ritonavir (TMC114/r) and efavirenz (EFV) in HIV-negative, healthy volunteers. METHODS: Volunteers received TMC114/r 300/100 mg twice daily for 6 days, and once daily on day 7 (session 1). After a 7-day washout period volunteers received EFV 600 mg once daily for 18 days (session 2), with coadministration of TMC114/r 300/100 mg twice daily from day 11-day 16 and TMC114/r once daily on day 17. RESULTS: When coadministered with TMC114/r, plasma concentrations of EFV were slightly increased. In the presence of TMC114/r, EFV minimum (Cmin) and maximum (Cmax) plasma concentrations increased by 15-17%, and by 21% for EFV area under the curve (AUC24h). TMC114/r and EFV coadministration resulted in TMC114 Cmin, Cmax and AUC12h decreases of 31%, 15% and 13%, respectively. No serious adverse events (AEs) or AEs leading to withdrawal were reported in this trial. Overall, TMC114/r and EFV coadministration was well tolerated. CONCLUSIONS: The clinical significance of the changes in AUC and Cmin seen with TMC114/r and EFV coadministration has not been established; this combination should be used with caution. Similar findings are expected with the approved TMC114/r 600/100 mg twice daily dose.     

Pharmacokinetic comparison of fast-disintegrating and conventional tablet formulations of risperidone in healthy volunteers

BACKGROUND: Difficulties with and resistance to tablet-taking are common in all patient groups and can exacerbate compliance problems and undermine treatment efficacy. In recent years, rapidly dissolving oral drug formulations have been developed to overcome problems related to swallowing difficulties. OBJECTIVE: The goal of this study was to evaluate the bioequivalence of a fast-disintegrating oral tablet of risperidone and the conventional oral tablet. METHODS: This was a randomized, open-label, 2-way crossover trial in which healthy volunteers received two 0.5-mg tablets of a fast-disintegrating oral risperidone formulation and two 0.5-mg tablets of conventional oral risperidone, each in a single administration. Blood samples for pharmacokinetic analysis of the active moiety (risperidone + 9-hydroxy-risperidone), risperidone, and its active metabolite 9-hydroxy-risperidone were obtained during a 96-hour period after dosing. Safety assessments included monitoring of adverse events, hematology and biochemistry tests of the sampled blood, urinalysis, blood pressure measurements, and electrocardiography. RESULTS: The bioequivalence assessment was based on pharmacokinetic and statistical analysis of data from 37 subjects who completed both treatment periods. The plasma concentration-time profiles of the active moiety, risperidone, and 9-hydroxy-risperidone were similar after intake of the 2 formulations. The fast-disintegrating tablet and the conventional tablet showed bioequivalence with respect to the active moiety, risperidone, and 9-hydroxy-risperidone. The 90% CIs for the mean treatment ratios of the log-transformed peak plasma concentration, area under the plasma concentration-time curve (AUC) to the last quantifiable time point, and AUC extrapolated to infinity were all within the predefined equivalence range from 80% to 125%. Twenty-eight of 50 (56%) subjects originally randomized reported adverse events, with a similar incidence for both treatments. All adverse events were mild, with somnolence and headache being the most frequently reported. No clinically relevant changes were observed in physical, biochemical, hematologic, or urinalysis variables during the study. CONCLUSION: In this study in healthy subjects, a single administration of two 0.5-mg fast-disintegrating risperidone tablets was bioequivalent to a single administration of two 0.5-mg conventional risperidone tablets.     

Pharmacokinetic interaction between single oral doses of diltiazem and sirolimus in healthy volunteers

AIM AND BACKGROUND: The pharmacokinetic interaction between sirolimus, a macrolide immunosuppressant metabolized by CYP3A4, and the calcium channel blocker diltiazem was studied in 18 healthy subjects. Several clinically important interactions have previously been reported for other immunosuppressive drugs that are metabolized by the same enzyme and for calcium antagonists. METHODS: Healthy subjects who were 20 to 43 years old participated in an open, three-period, randomized, crossover study of the pharmacokinetics of a single 10-mg oral dose of sirolimus, a single oral 120-mg dose of diltiazem, and the two drugs given together. The three study periods were separated by a 21-day washout phase. RESULTS: The geometric mean (90% confidence interval) whole blood sirolimus area under the plasma concentration time-curve increased 60% (35%-90%), from 736 to 1178 ng x h/mL, and maximum concentration increased 43% (14%-81%), from 67 to 96 ng/mL, with diltiazem coadministration, whereas the mean elimination half-life of sirolimus decreased slightly, from 79 to 67 hours. Apparent oral clearance and volume of distribution of sirolimus decreased with 38% and 45%, respectively, when sirolimus was given with diltiazem. The plasma maximum concentration and area under the plasma concentration-time curve of diltiazem, desacetyldiltiazem, and desmethyldiltiazem were unchanged after coadministration of sirolimus, and no potentiation of the effects of diltiazem on diastolic or systolic blood pressure or on the electrocardiographic parameters was seen. CONCLUSIONS: Single-dose diltiazem coadministration leads to higher sirolimus exposure, presumably by inhibition of the first-pass metabolism of sirolimus. Because of the pronounced intersubject variability in the extent of the sirolimus-diltiazem interaction, whole blood sirolimus concentrations should be monitored closely in patients treated with the two drugs.     

Pharmacokinetic study of tenofovir disoproxil fumarate combined with rifampin in healthy volunteers

Tenofovir disoproxil fumarate (tenofovir DF) was studied in combination with rifampin in 24 healthy subjects in a multiple-dose, open-label, single-group, two-period study. All subjects were given tenofovir DF at 300 mg once a day (QD) from days 1 to 10 (period 1). From days 11 to 20 the subjects received tenofovir DF at 300 mg combined with rifampin at 600 mg QD (period 2). The multiple-dose pharmacokinetics of tenofovir (day 10 and 20) and rifampin (day 20) were assessed. The drug-related adverse events (AEs) experienced during this study were mostly mild. Only one grade 3 AE possibly or probably related to the treatment (raised liver enzyme levels) occurred during period 2; the subject was withdrawn from the study. Pharmacokinetic data for 23 subjects were thus evaluable. Point estimates for the mean ratios of tenofovir with rifampin versus tenofovir alone for the area under the concentration-time curve from time zero to 24 h (AUC(0-24)), the maximum concentration of drug in plasma (C(max)), and the minimum concentration of drug in plasma (C(min)) were 0.88, 0.84, and 0.85, respectively. The 90% classical confidence intervals for AUC(0-24), C(max), and C(min) were 0.84 to 0.92, 0.78 to 0.90, and 0.80 to 0.91, respectively, thus suggesting pharmacokinetic equivalence. Similarly, coadministration of rifampin and tenofovir DF did not result in changes in the values of the tenofovir pharmacokinetic parameters. For rifampin, the values of the pharmacokinetic parameters found in this study were comparable to those found in the literature, indicating that tenofovir DF has no effect on the pharmacokinetics of rifampin. In conclusion, adaptation of either the rifampin or the tenofovir DF dose for the simultaneous treatment of tuberculosis and human immunodeficiency virus (HIV) infection in HIV-infected patients is probably not required.