The bioavailability and pharmacokinetics of oral and depot intramuscular haloperidol in schizophrenic patients

In a four-segment long-term (greater than or equal to 6 mo) study, patients with schizophrenia received oral haloperidol in single daily doses and subsequently depot intramuscular (IM) haloperidol decanoate q28d. For each route of administration, a period of stabilization was followed by a maintenance period. Dosages for both oral haloperidol and IM haloperidol decanoate were determined on the basis of the patient's past psychiatric history and clinical response during the stabilization period. To characterize the concentration-time profile of the two routes of administration, blood samples were obtained on two separate occasions at steady state during maintenance dosing for each route of administration. Examination of values for cumulative area under the plasma concentration-time curves (AUC) to each sampling time indicated a sustained release of haloperidol from the intramuscularly administered haloperidol decanoate. Dose ranges during maintenance periods were 5-35 mg/d for oral haloperidol (mean, 17 mg/d), and 75-500 mg/28 d for IM haloperidol decanoate (mean, haloperidol decanoate was 243 mg equivalents of haloperidol/28 d). The ratio of long-acting to daily oral doses during maintenance therapy ranged from 9.4:1.0 to 15.0:1.0 (mean, 14.1:1.0). At these ratios, plasma concentration data showed that haloperidol decanoate gave lower values than did oral haloperidol for peak plasma, minimum plasma, and mean steady-state plasma concentrations. The absolute concentration swing was significantly less for decanoate than for the oral drug. Dose-normalized AUC values were compared determine the IM dose of haloperidol decanoate that would have yielded haloperidol plasma concentrations equivalent to those resulting from daily oral administration of haloperidol for 28 days.(ABSTRACT TRUNCATED AT 250 WORDS)     

Dose- and time-dependent pharmacokinetics of midostaurin in patients with diabetes mellitus

Midostaurin is a novel potent inhibitor of both protein kinase C and the major receptor for vascular endothelial growth factor involved in angiogenesis, presenting a rationale for its use in diabetic retinopathy. This study evaluated the safety and pharmacokinetics of midostaurin following multiple oral doses of midostaurin for 28 days at 4 dose levels (25 mg bid, 50 mg bid, 75 mg bid, 75 mg tid), as well as a single oral 100-mg dose in patients with diabetes mellitus (n = 9-13 per dose cohort). Pharmacokinetic parameters were determined on days 1 and 28 based on the plasma concentrations of midostaurin and its metabolites, CGP62221 and CGP52421. The plasma exposures (C(max) and AUC(0-tau)) of midostaurin and metabolites increased less than proportionally over the dose range of 25 to 100 mg, showing a 2.2-fold increase after the first dose. Midostaurin concentrations increased during the first 3 to 6 days of dosing, then declined with time (by 30%-50%) until a steady state was achieved, representing an average accumulation factor (R) of 1.7. CGP62221 showed a similar concentration-time pattern as midostaurin (R = 2.5), but CGP52421 accumulated significantly (R = 18.8). A high-fat meal was found to significantly increase the C(max) and AUC(0-12 h) of midostaurin by 1.5-fold (P = .04) and 1.8-fold (P = .01), respectively, compared with taking the drug after an overnight fast. Midostaurin administered at 50 to 225 mg/day appeared to be generally safe in this group of patients. The most common treatment-related adverse events (eg, loose stools, nausea, vomiting, and headache) were found to be dose related, and the frequency increased markedly above the 150-mg/day dose level.     

Evaluation of safety and pharmacokinetics of consecutive multiple-day dosing of palonosetron in healthy subjects

This study evaluated the safety and pharmacokinetics of consecutive multiple-day dosing of palonosetron. Sixteen healthy subjects received an intravenous bolus dose of palonosetron 0.25 mg (n = 12) or placebo (n = 4) daily for 3 consecutive days. Safety was evaluated throughout the study. Serial plasma samples were collected on days 1 and 3 for pharmacokinetic determinations. Three days of dosing with palonosetron 0.25 mg was safe and well tolerated. There were no clinically significant changes from baseline in laboratory values, vital signs, physical examinations, or electrocardiogram intervals. Plasma palonosetron concentrations declined in a biphasic manner, measurable up to 168 hours after dosing on day 3. Mean terminal phase elimination half-life after day 3 dosing was 42.8 hours. The 2.1-fold accumulation of palonosetron in plasma following 3 daily doses was predictable based on elimination half-life of approximately 40 hours, and the maximum plasma concentration remained below the maximum plasma concentration previously observed after a single, well-tolerated 0.75 mg intravenous bolus dose of palonosetron.     

Pharmacokinetics of pemoline in plasma, saliva and urine following oral administration.

1 Pemoline concentrations were measured in plasma and saliva following a single oral dose (37.5 or 50.0 mg) to healthy volunteers. In addition urinary excretion rates and cumulative urinary excretion of the parent compound and its oxazolidinedione metabolite were determined. 2 The plasma curves exhibited a mean elimination half-live of 11.0 +/- 1.2 h (n=4). Peak levels were reached at 2.7 +/- 0.6 h (n=4). The saliva concentrations were about 50% lower than the corresponding plasma concentrations during the elimination phase. During the absorption phase irregularities in the saliva to plasma concentration ratios were observed. 3 In urine 47.0 +/- 8.4% of the dose (n=6) administered was excreted as unchanged drug and only 3.7 +/- 0.8% (n=3) as the oxazolidinedione metabolite. Urinary half-lives were slightly shorter than the corresponding plasma half-lives.     

Pharmacokinetics of intravenous itraconazole followed by itraconazole oral solution in patients with human immunodeficiency virus infection.

This randomized, open-label, comparative study assessed the pharmacokinetics and safety of intravenous and oral hydroxypropyl-beta-cyclodextrin (HP-beta-CD) solutions of itraconazole in patients with advanced human immunodeficiency virus (HIV) infection. All patients received 1-hour intravenous infusions of itraconazole 200 mg twice dailyfor 2 days, then once dailyfor 5 days. Patients were then randomized to receive itraconazole oral solution, 200 mg twice daily or 200 mg once daily, for a further 28 days. Itraconazole was solubilized by HP-beta-CD in both intravenous and oral solutions, so HP-beta-CD concentration in plasma was measured. Thirty-two patients were enrolled and analyzed (n = 32 for intravenous treatment, 32 completed; n = 16 for oral once daily, 15 completed; n = 16 for oral twice daily, 12 completed). Steady-state plasma concentrations of itraconazole and hydroxyitraconazole were reached by days 3 and 6, respectively. After intravenous dosing, mean trough plasma concentrations of itraconazole and hydroxyitraconazole were 906 ng/ml and 1,690 ng/ml, respectively. During oral dosing, mean trough plasma concentrations of itraconazole and hydroxyitraconazole were maintained or increased in the 200 mg twice-dailygroup but fell with the 200 mg once-daily oral dose. Itraconazole was generally well tolerated and had a favorable safetyprofile; minor changes in hematology variables were noted during the intravenous phase, and HP-beta-CD was cleared rapidly, mostly in urine. Twenty-eight patients (88%) experienced at least one adverse event; no adverse event was severe, and only seven were definitely related to itraconazole. In conclusion, itraconazole 200 mg given intravenously twice daily for 2 days, then once daily for 5 days, rapidly achieves amean steady-state trough concentration of itraconazole of over 250 ng/ml, which is associated with clinic outcome and is effectively maintained with itraconazole oral solution 200 mg twice daily in patients with advanced HIV infection.     

Pharmacokinetics of a sustained-release theophylline formulation.

1 Plasma theophylline concentrations following administration of sustained-release (SR) theophylline tablets were determined in ten healthy volunteers using a dose of 190 mg or 380 mg 12 hourly. 2 The plasma theophylline levels during the first 12 h period confirmed the sustained-release formulation characteristics, with the plasma drug concentrations reaching a plateau for the last 6 hours. 3 During the fifth 12 h dosing period the mean maximum and minimum plasma theophylline concentrations were 7.25 and 4.30 microgram/ml after 190 mg SR theophylline 12 hourly (n = 6) and 12.96 and 7.36 microgram/ml after 380 mg 12 hourly (n = 5), although there was marked between-subject variation in plasma theophylline concentrations. 4 One subject withdrew from the study due to side effects, which were more common when the higher dose of SR theophylline was given.     

Pharmacokinetics of atorvastatin and its hydroxy metabolites in rats and the effects of concomitant rifampicin single doses: relevance of first-pass effect from hepatic uptake transporters, and intestinal and hepatic metabolism.

Pharmacokinetic coadministration experiments with atorvastatin (ATV) and rifampicin (RIF) in rats were performed to investigate the potential involvement of hepatic uptake transporters, Oatps (organic anion-transporting polypeptides), during hepatic drug elimination, as an in vivo extension of our recently published cellular and isolated perfused liver studies. ATV was administered orally (10 mg/kg) and intravenously (2 mg/kg) to rats in the absence and presence of a single intravenous dose of RIF (20 mg/kg), and pharmacokinetic parameters were compared between control and RIF-treatment groups. RIF markedly increased the plasma concentrations of ATV and its metabolites when ATV was administered orally. The area under the plasma concentration-time curve (AUC(0-infinity)) for ATV also increased significantly after intravenous dosing of ATV with RIF, but the extent was much less than that observed for oral ATV dosing. Significant increases in plasma levels were observed for both metabolites as well. The 7-fold higher AUC ratio of metabolites to parent drug following oral versus intravenous ATV dosing suggests that ATV undergoes extensive gut metabolism. Both hepatic and intestinal metabolism contribute to the low oral bioavailability of ATV in rats. In the presence of RIF, the liver metabolic extraction was significantly reduced, most likely because of RIF's inhibition on Oatp-mediated uptake, which leads to reduced hepatic amounts of parent drug for subsequent metabolism. Gut extraction was also significantly reduced, but we were unable to elucidate the mechanism of this effect because intravenous RIF caused gut changes in availability. These studies reinforce our hypothesis that hepatic uptake is a major contributor to the elimination of ATV and its metabolites in vivo.     

Physiological disposition of CGS 16617 in rat, dog, and man

The disposition and metabolism of CGS 16617 (3-[(5-amino-1-carboxy-1S-pentyl)amino],2,3,4,5-tetrahydro-2-oxo-3S-1H-1 - benzazepine-1-acetic acid), and angiotensin l-converting enzyme inhibitor, were investigated in rats, dogs, and man. In rats, a single oral dose of 10 mg/kg 14C-CGS 16617 afforded peak plasma concentrations of drug between 0.5 and 6 hr of dosing. The AUC was on average 9.6% of that after iv administration of the same dose, indicating low oral absorption of the drug. The apparent volumes of distribution, V1 and Vdss, were 0.45 and 2.5 liters/kg, respectively. Disappearance of the drug from plasma after the iv dose was biphasic, with mean half-lives of 0.5 and 13 hr, respectively, for the lambda 1 and lambda 2 phases. After single iv doses (10 mg/kg) to dogs and rats, 14CGS 16617 was almost exclusively eliminated by the renal route, with urinary recoveries of greater than 90% of dose. The same dose administered orally gave urinary recoveries of less than 10% of the dose in rats and about 15% in the dog. The remainder of the dose was eliminated in the feces. Bile duct-cannulated rats excreted less than 3% of an oral 10 mg/kg dose in the bile, in 24 hr. In man (N = 4), a single oral dose of 100 mg 14C-CGS 16617 resulted in peak plasma concentrations of 0.02-0.07 microgram of drug eq/ml between 4 and 6 hr of dosing. The mean terminal half-life was estimated at 81 hr.(ABSTRACT TRUNCATED AT 250 WORDS)     

Plasma concentrations of buprenorphine 24 to 72 hours after dosing.

BACKGROUND: This study evaluated plasma buprenorphine concentrations 24-72 h following sublingual administration of a dose of buprenorphine solution, ranging from 16 mg/70 kg to 44 mg/70 kg, administered on a daily or thrice-weekly schedule. Additionally, this study evaluated the effects of different thrice-weekly buprenorphine dose schedules on opiate use and withdrawal symptoms. METHODS: Opiate dependent subjects (n = 10) were maintained in an outpatient clinic for two 3-week periods at each of three thrice-weekly buprenorphine dose schedules (providing a weekly total buprenorphine dose of 64, 84 and 112 mg) and for 1 week of a daily buprenorphine dose of 16 mg/70 kg. Plasma samples were obtained 24, 48 and 72 h following administration of buprenorphine. Urine samples were also collected and opiate withdrawal symptoms, agonist effects and the use of heroin, cocaine, alcohol and other drugs, were assessed. RESULTS: Plasma levels showed a wide range of intra- and inter-subject variability. Nonetheless, higher doses of buprenorphine resulted in higher plasma concentrations at each time point and plasma concentration decreased with time. There were no significant differences in heroin use across dosing. Rates of withdrawal symptoms were low and did not differ across dosing schedules. CONCLUSIONS: In the two highest dose schedules, plasma levels 72 h following the administration of the highest dose and at 48 h after the lower dose, were comparable to plasma concentrations at 24 h following daily administration of 16 mg/70 kg of buprenorphine.     

Chondrotoxicity of ciprofloxacin in immature Beagle dogs: immunohistochemistry, electron microscopy and drug plasma concentrations

The systemic effects of ciprofloxacin in immature Beagles were studied. Dogs of 10-11 weeks were dosed orally for 5 days with 0 (n=3), 30 (n=5) and 200 (n=5) mg ciprofloxacin/kg body wt. Plasma concentrations were measured by high-performance liquid chromatography (HPLC) 1 h after dosing (assuming to be peak concentrations). In view of the high doses used, the plasma concentrations were rather low and declined during the study period. For example, plasma concentrations in the high dose group were 6.6 +/- 0.9 mg/l (day 1), 3.9 +/- 1.4 mg/l (day 3), and 2.6 +/- 1.6 mg/l (day 5). In control dogs and in dogs treated with the low dose of ciprofloxacin no pathological changes were seen by light microscopy. However, cleft formation and erosions were observed in joint cartilage from two of five dogs treated with 200 mg/kg. It is noteworthy that despite the high dose used cartilage lesions were not detectable in all five dogs of this group by light microscopy. Using antibodies against cell membrane receptors (e.g. the alpha(5)beta(1)-integrin) or matrix components (fibronectin, collagen II) the articular cartilage effects were studied in detail by immunohistochemistry. The most sensitive alteration was an increase in fibronectin which was detectable in the vicinity of the lesions in cartilage samples from the group of dogs administered the high dose. No clear-cut changes were seen with the use of antibodies against other matrix components. Electron microscopy revealed typical alterations in chondrocytes from dogs treated with ciprofloxacin: e.g., swollen mitochondria and enlarged rough endoplasmic reticulum. These changes were much more pronounced in dogs from the high dose group than in dogs from the low dose group. Our main conclusion is that after oral administration ciprofloxacin exhibits rather low chondrotoxicity, even in the most sensitive species known to date. This correlates with the findings in humans that ciprofloxacin seems to be less chondrotoxic than pefloxacin or other quinolones.     

Pharmacokinetic profiles in rats after intravenous, oral, or dermal administration of dapsone.

Dapsone is a potent anti-inflammatory and antibacterial agent that has been used extensively in the oral treatment of leprosy and dermatitis herpetiformis. This study compared the pharmacokinetic profile of dapsone in rats given a single oral or i.v. 12 mg/kg dose (n = 8/group) or a single dermal application of 12 or 60 mg/kg (n = 12/group) in an aqueous gel application medium containing 10 or 25% diethylene glycol monoethyl ether (DGME). Blood samples (200 microl) were collected via tail vein from each rat and pooled at intervals up to the 24-h period. A terminal blood sample was collected by cardiac puncture from each animal. Plasma concentrations of dapsone were determined by liquid chromatography atmospheric pressure ionization tandem mass spectroscopy. There was no treatment-related overt toxicity observed in any of the animals. Peak levels were reached 1 h after oral dosing (4890 ng/ml), and 6 to 8 h after dermal application, with Cmax values of 1.62, 5.56, and 12.8 ng/ml, for 12 mg/kg at 10 or 25% DGME, and for 60 mg/kg at 25% DGME, respectively. Bioavailability was calculated at 78% after oral dosing and <1% after dermal application. Apparent elimination half-lives (t(1/2))s were similar after i.v. and oral dosing. Both the calculated area under the plasma concentration versus time curve up to 24 h and Cmax values were 3- to 4-fold higher in the dermal application group administered 12 mg/kg dapsone in 25 versus 10% DGME gel, whereas the calculated area under the plasma concentration versus time curve up to 24 h and Cmax values for the 60 mg/kg group were only 3.3- and 2.3-fold greater than those obtained after application of 12 mg/kg in 25% DGME. These results show that both systemic exposure and peak plasma concentrations of dapsone are minimized by dermal versus oral administration of the compound.     

Effects of smoking, CYP2D6 genotype, and concomitant drug intake on the steady state plasma concentrations of haloperidol and reduced haloperidol in schizophrenic inpatients.

The effects of smoking, CYP2D6 genotype, and concomitant use of enzyme inducers or inhibitors on the steady state plasma concentrations of haloperidol (HAL) and reduced haloperidol (RHAL) were evaluated in 92 schizophrenic inpatients. All but three of these patients received concomitant medication, in many cases with drugs potentially interacting with HAL. Of the 92 patients, 63 were treated orally with HAL in a daily dose of 0.4 to 50 mg; 29 patients were treated intramuscularly with a daily equivalent dose of HAL decanoate (expressed as HAL) of 1.8 to 17.9 mg. A wide interindividual variation in HAL dose and in steady state plasma concentrations of HAL and RHAL was observed. In the patients treated orally, the daily oral dose was about 4 times higher and the dose-normalized HAL (but not RHAL) plasma concentrations were significantly lower in smokers (n = 40) than in nonsmokers (n = 23) (p < 0.01). The dose-normalized RHAL (but not HAL) plasma concentrations and the RHAL/HAL ratio were significantly higher in poor metabolizers (PMs) than in extensive metabolizers (EMs). There was a trend toward an effect of potentially interacting drugs (inducers or inhibitors) on dose, dose-normalized HAL and RHAL plasma concentrations, and the RHAL/HAL ratio. In the patients treated intramuscularly, the dose-normalized HAL (but not RHAL) plasma concentrations were significantly lower in smokers than in nonsmokers, but no differences in doses were observed. This naturalistic study of modest sample size in a polymedicated population shows an effect of smoking and CYP2D6 genotype (and to a lesser extent, of interacting drugs) on the kinetics of HAL.     

Steady-state pharmacokinetics and dose proportionality of troglitazone and its metabolites.

This study evaluated the steady-state pharmacokinetics and dose proportionality of troglitazone, metabolite 1 (sulfate conjugate), and metabolite 3 (quinone metabolite) following administration of daily oral doses of 200, 400, and 600 mg troglitazone for 7 days (per dosing period) to 21 subjects. During each dosing period, plasma samples were collected predose on days 1, 5, 6 and 7 and serially for 24 hours on day 7. Steady-state plasma concentrations for troglitazone, metabolite 1, and metabolite 3 were achieved by day 7. Troglitazone was rapidly absorbed with mean tmax values of 2.7 to 2.9 hours. Mean Cmax and AUC(0-24) values for troglitazone, metabolite 1, and metabolite 3 increased proportionally with increasing troglitazone doses over the clinical dose range of 200 mg to 600 mg administered once daily. Mean troglitazone CL/F, percent fluctuation, and AUC ratios of metabolite 1 and metabolite 3 to troglitazone were similar across dose groups. These data suggest that the pharmacokinetics and disposition of troglitazone and its metabolites are independent of dose over the dose range studied. Thus, troglitazone, metabolite 1, and metabolite 3 displayed linear pharmacokinetics at steady-state.     

Importance of oral dosing rate on the hemodynamic and pharmacokinetic profile on nilvadipine

Nilvadipine was administered as an oral solution formulation to 12 normotensive subjects in a three-way randomized crossover study at a dose of 16 mg as three different dosing regimens: 1) as a single 16 mg dose, 2) as a 1.6 mg dose given hourly for 10 doses, and 3) as an initial dose of 4.8 mg, followed by 1.6 mg doses given every hour for seven additional doses. After each dose, clinical effects, hemodynamic changes and the pharmacokinetic profile of the drug were determined. The mean maximum changes in diastolic (DBP) and systolic (SBP) blood pressure and heart rate (HR) after dosing regimens 1, 2, and 3 were: -33, -13 and +46%; -17, -14 and +38%; and -24, -14 and +36%, respectively. There was a relationship between the changes in DBP and HR and plasma concentrations of nilvadipine only after dosing regimen 1. The effect-concentration relationships were fit to a modified Emax model. There was no relationship between the change in SBP and plasma concentration after any of the dosing regimens. While there were no significant differences in the mean area under the plasma concentration-time curve (AUC0----infinity) between dosing regimens 2 (38.7 ng.hr/mL) and 3 (42.1 ng.hr/mL) (P greater than 0.05), the mean AUC0----infinity after regimen 1 (76.3 ng.hr/mL) was significantly greater than after dosing regimens 2 or 3 (P less than 0.05). The mean maximal plasma concentrations (Cmax) were 31.6, 1.3 and 6.3 ng/mL after dosing regimens 1, 2 and 3, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)     

Human scalp hair as evidence of individual dosage history of haloperidol: prospective study

The concentration of haloperidol in hair was measured by radioimmunoassay after hairs were dissolved in 2.5 N NaOH solution and the drug was extracted. In patients to whom haloperidol had been administered at fixed daily doses for more than 1 month, and in whom therapy had been just discontinued (group A, n = 5) or the doses cut to half (group B, n = 3), hairs were collected when the dose was changed and at 1 and 2 or 3 months thereafter. A few strands of hair collected on each occasion were cut into 1-cm-long portions from the roots, and the haloperidol concentration was measured in each portion. When hairs were assumed to grow at a rate of 1-1.5 cm/month, the portion of hair that reflected the change of dose was observed to move upward along the hair length in all patients of group A. However, these phenomena were less obvious in group B. These results indicate that at the least, hair could serve as an indicator of individual exposure or nonexposure to haloperidol and could yield retrospective information. In rats whose hairs had been removed by plucking from an area on the back, either saline or 1 mg/kg of haloperidol (i.p., b.i.d.) was administered for 2 weeks (first period), followed by 0, 0.5, 1, or 2 mg/kg b.i.d. for the subsequent 2 weeks (second period). At the end of each period, hairs that had grown in the plucked area were collected. Within-groups, haloperidol levels in hairs collected at the end of each period corresponded to the doses given.(ABSTRACT TRUNCATED AT 250 WORDS)     

The safety and pharmacokinetics of quetiapine when coadministered with haloperidol, risperidone, or thioridazine

The effects of haloperidol, risperidone, and thioridazine on the pharmacokinetics and side-effect profile of quetiapine were investigated in 36 patients with schizophrenia, schizoaffective disorder, or bipolar disorder in a single-center, two-period, multiple-dose, open-label, randomized trial. Over a one-to two-week period, quetiapine doses were escalated to 300 mg twice daily (bid). Patients were then treated for at least 7 days at the target quetiapine dose and subsequently entered into the combination therapy period, receiving haloperidol (7.5 mg, bid), risperidone (3 mg, bid), or thioridazine (200 mg, bid) for 8.5 days (after 3 days of dose escalation). Key assessments included the pharmacokinetics of quetiapine at steady state (area under the curve within a dosing interval [AUCtSS], maximum [CmaxSS], and minimum [CminSS] observed plasma concentrations, and oral clearance [Cl/f]), as well as the UKU Side Effect Rating Scale scores and safety evaluations.Neither risperidone nor haloperidol had significant effects on quetiapine pharmacokinetics. However, thioridazine produced statistically significant changes, decreasing the least squares means values of the AUCtSS, CmaxSS, and CminSS by 40%, 47%, and 31%, respectively, and increasing Cl/f by 68%. Increases in the following adverse events were noted during coadministration: somnolence (risperidone), insomnia and dry mouth (all three coadministered therapies), and dizziness (thioridazine). UKU side effect items that became worse in >or= 25% of patients during each coadministration period included sedation and increased sleep duration. Results of laboratory tests, electrocardiograms, and vital sign measurements revealed few clinically important changes.Clinical stability can be maintained with good tolerability during the transition from quetiapine monotherapy to periods of coadministration with haloperidol, risperidone, or thioridazine. Coadministration of either haloperidol or risperidone did not have any important effects on the steady-state pharmacokinetics of quetiapine. Thioridazine significantly increased the oral clearance of quetiapine. Increased doses of quetiapine may be necessary to control psychotic symptoms when thioridazine is coadministered with quetiapine.     

Flecainide: single and multiple oral dose kinetics, absolute bioavailability and effect of food and antacid in man.

The kinetics of flecainide after single intravenous (2 mg kg-1) and oral (200 mg) dosing, absolute bioavailability, effects of food and aluminium hydroxide on flecainide absorption and steady-state kinetics following twice daily oral dosing (200 mg) have been evaluated in ten healthy subjects. Absolute bioavailability of oral flecainide averaged 70% (range 60-86%). Rate and extent of flecainide absorption were not significantly affected by food nor by concomitantly administered aluminium hydroxide. The apparent volume of distribution of 5.5 +/- 0.3 l kg-1 indicates wide distribution of flecainide in tissues. Estimated elimination half-lives from plasma data averaged 9.3 to 12.4 h (single oral dose studies), 11.8 h (single i.v. dose), and 11.5 h (multiple oral dose). Half-lives calculated from urinary excretion data corresponded well with those calculated from plasma data. Flecainide elimination takes place both by nonrenal (metabolic) clearance and renal excretion of the intact drug involving glomerular filtration and active tubular secretion. Following i.v. dosing CLNR and CLR averaged respectively 3.24 +/- 0.80 and 2.38 +/- 0.49 ml min-1 kg-1. After 200 mg twice daily oral treatment steady state was reached within 3-4 days with trough and peak plasma levels on day 8 of 457 and 662 ng ml-1, which are well within the therapeutic range.     

The tolerability of intramuscular ziprasidone and haloperidol treatment and the transition to oral therapy

The intramuscular (i.m.) formulation of ziprasidone offers promise as an alternative to conventional i.m. agents for the short-term management of agitated patients with psychosis. This 7-day, randomized, open-label study evaluated the tolerability of ziprasidone i.m. and haloperidol i.m. in hospitalized patients with a psychotic disorder and moderate psychopathology. Patients received three fixed doses of ziprasidone i.m. 5 mg qid (n=69), 10mg qid (currently maximum recommended daily dose in USA; n=71), 20mg qid (n=66), or flexible-dose/ flexible-schedule haloperidol i.m. up to 10 mg bid-qid (n=100) for 3 days. This was followed by oral treatment with the same medication for 4 days. Ziprasidone i.m. was associated with a notably lower burden of movement disorders than haloperidol i.m. (mean 11 mg/day). No bradycardia, sinus pauses, disinhibition, confusion, excessive sedation or respiratory depression was observed with ziprasidone. No safety issues were identified with the coadministration of lorazepam with the i.m. formulations of either agent. All three ziprasidone i.m. doses and haloperidol i.m. maintained control of symptoms and, following the transition to oral treatment, symptoms remained controlled. Ziprasidone i.m. 5,10, and 20 mg qid, given for 3 days were well tolerated. The transition from i.m. to oral ziprasidone was well tolerated with continuing maintenance of symptom control.     

Multiple dose pharmacokinetics and concentration effect relationship of the orally active renin inhibitor remikiren (Ro 42-5892) in hypertensive patients

1 Three double-blind, randomized, placebo controlled, multiple oral dose studies in patients with mild to moderate hypertension were performed to study tolerability, pharmacodynamics and pharmacokinetics of remikiren. Doses of 100-800 mg remikiren or placebo were given over 8 days to altogether 144 patient volunteers. In some cases (n = 46) single i.v. doses of 100 mg were administered 4 h after the last oral dose. Plasma remikiren concentrations, plasma renin activity and immunoreactive renin concentrations were measured. Pharmacokinetic parameters were estimated using model independent techniques and the concentration-effect relationship was evaluated using population pharmacometric methods. 2 In most patients no distinct absorption and disposition phase could be identified, since plasma concentrations fluctuated widely over a period of approximately 10 h. Peak plasma concentrations (Cmax) were achieved within 0.25-2 h postdose. Mean Cmax values (on the first and last day of oral treatment) were in the magnitude of 4-6 ng ml(-1) (200 mg), 23-27 ng ml(-1) (300 mg), 65-83 ng ml(-1) (600 mg) and 47-48 ng ml(-1) (800 mg). Cmax and AUC0-t values were clearly different for different doses within single studies. Intersubject variability in pharmacokinetic parameters was much higher than intrasubject variability. No drug accumulation in plasma was apparent. 3 Inhibition of the angiotensin I production rate correlated well with plasma drug concentrations according to the Emax-model. An IC50 value of 0.5 ng ml(-1) (0.8 nM) was estimated. No correlation between blood pressure changes on the last day of oral treatment and either plasma remikiren concentrations or plasma renin inhibition was found.