Kinetics of medroxalol, a beta- and alpha-adrenoceptor antagonist

Eight healthy men received single oral doses of 400, 800, and 1200 mg medroxalol and a single intravenous dose of 1 mg per kg body weight on four occasions separated by at least 2 wk. Plasma medroxalol concentrations were assayed up to 24 hr after each dose by a specific high-pressure liquid chromatographic assay. Urinary excretion of parent compound was determined as well. Following oral doses medroxalol reached peak plasma concentrations within 2.5 to 3 hr. The t 1/2 of the terminal decay phase was 11.1 hr. Mean apparent volume of distribution (aVD) was between 11.2 and 16.4 l/kg, and mean total body clearance (ClT) was between 0.73 and 0.99 l hr-1 kg-1. Mean urinary recovery of parent drug within 48 hr was 2.3%, 3.9%, and 3.6% after the oral doses compared to 8.2% after the intravenous dose. Bioavailability estimated from AUC was 27.2% after 400 mg, 31.3% after 800 mg, and 37.4% after 1200 mg by mouth. Since aVD, t 1/2, ClT, and urinary excretion did not differ significantly after the three oral doses, medroxalol kinetics appear to follow a dose-linear model.     

Dose effects associated with rivastigmine transdermal patch in patients with mild-to-moderate Alzheimer's disease

Aim: The cholinesterase inhibitor rivastigmine is available in both oral and transdermal forms. The efficacy of oral rivastigmine appears to be dose‐dependent. The current analysis investigates the effect of dose on the efficacy of the rivastigmine transdermal patch. Methods: This was a retrospective analysis of a large, international, 24‐week, randomised, placebo‐ and active‐controlled trial (IDEAL, CENA713D2320) of rivastigmine in patients with mild‐to‐moderate Alzheimer’s disease (AD). Patients received the 9.5 mg/24 h rivastigmine patch, the 17.4 mg/24 h rivastigmine patch, 12 mg/day rivastigmine capsules or placebo. Changes from baseline at week 24 on the AD Assessment Scale–cognitive subscale (ADAS‐cog), AD Cooperative Study–Clinical Global Impression of Change (ADCS‐CGIC) and the AD Cooperative Study–Activities of Daily Living (ADCS‐ADL) scale were calculated based on the patient’s mode and last prescribed patch dose. The analysis included the 4.6 mg/24 h and 13.3 mg/24 h patch doses, for which efficacy data have not previously been reported. Results: Significant differences (p < 0.05 vs. placebo) were seen on the ADAS‐cog and ADCS‐ADL for all mode rivastigmine patch doses (except 4.6 mg/24 h) and all last prescribed rivastigmine patch doses (except 4.6 mg/24 h and 13.3 mg/24 h). Patients with a last prescribed/mode patch dose of 9.5 mg/24 h and 13.3 mg/24 h showed significant improvements (p < 0.05 vs. placebo) on the ADCS‐CGIC. Conclusion: Rivastigmine patch doses higher than 9.5 mg/24 h may offer additional benefits. The 13.3 mg/24 h patch is worthy of further investigation.     

Short versus Long Infusion of Meropenem in Very-Low-Birth-Weight Neonates

Prolonged infusion of meropenem has been suggested in studies with population pharmacokinetic modeling but has not been tested in neonates. We compared the steady-state pharmacokinetics (PK) of meropenem given as a short (30-min) or prolonged (4-h) infusion to very-low-birth-weight (gestational age, <32 weeks; birth weight, <1,200 g) neonates to define the appropriate dosing regimen for a phase 3 efficacy study. Short (n = 9) or prolonged (n = 10) infusions of meropenem were given at a dose of 20 mg/kg every 12 h. Immediately before and 0.5, 1.5, 4, 8, and 12 h after the 4th to 7th doses of meropenem, blood samples were collected. Meropenem concentrations were measured by ultrahigh-performance liquid chromatography. PK analysis was performed with WinNonlin software, and modeling was performed with NONMEM software. A short infusion resulted in a higher mean drug concentration in serum (C(max)) than a prolonged infusion (89 versus 54 mg/liter). In all but two patients in the prolonged-infusion group, the free serum drug concentration was above the MIC (2 mg/liter) 100% of the time. Meropenem clearance (CL) was not influenced by postnatal or postmenstrual age. In population PK analysis, a one-compartment model provided the best fit and the steady-state distribution volume (V(ss)) was scaled with body weight and CL with a published renal maturation function. The covariates serum creatinine and postnatal and gestational ages did not improve the model fit. The final parameter estimates were a V(ss) of 0.301 liter/kg and a CL of 0.061 liter/h/kg. Meropenem infusions of 30 min are acceptable as they balance a reasonably high C(max) with convenience of dosing. In very-low-birth-weight neonates, no dosing adjustment is needed over the first month of life.     

Serum disopyramide concentrations and suppression of ventricular premature contractions

Serum disopyramide determinations and 24-hour Holter monitoring were performed in 20 cardiac subjects with ventricular premature contractions (VPCs) after the first, seventeenth, and thirty-seventh doses of disopyramide, 100 mg (10 subjects; low-dose group) or 200 mg (10 subjects; high-dose group) every 6 hr for 10 days to assess the ability of single- or first-dose data to predict serum disopyramide concentrations at steady state and the relationship between steady-state serum disopyramide concentrations and VPC suppression. Control Holter recordings were made for 48 hr in each subject. There were strong correlations in both groups between data for the AUC over 0 to 6 hr for the first dose (AUC60) and average (C ss) and trough (C min) steady-rate serum disopyramide concentrations after the seventeenth and thirty-seventh doses and the two combined. C ss and C min were related to AUC60 by the following expressions for both dosage groups: C ss = 0.22 AUC60 + 0.90 and C min = 0.20 AUC60 + 0.70. There were good correlations between 6-hr serum disopyramide concentration after the first dose and C ss and C min. There was strong correlation between overall average steady-state serum disopyramide concentration and suppression of VPC frequency. The relationship between VPC suppression and overall average trough serum disopyramide concentration at steady state, on the other hand, was weak.     

Pharmacokinetics in Non-Insulin-Dependent Diabetics of the Aldose Reductase Inhibitor, Zopolrestat

The pharmacokinetics of zopolrestat have been examined in non-insulin-dependent diabetic patients after oral administration of a single dose of 1000 mg zopolrestat. T(max) ranged from 2 to 4 h with a mean C(max) of 100 &mgr;g ml(minus sign1). Mean plasma half-life of zopolrestat was 26.9 h. The same patients were also administered oral doses of 1000 mg day(minus sign1) for 10 consecutive days. Mean T(max) was 4.3 h and mean C(max) was 208 &mgr;g ml(minus sign1). Plasma accumulation, the ratio of AUC((0--24)) for the last dose to AUC((0--24)) for the first dose, was 2.67. Apparent oral clearance was 5.71 ml min(minus sign1) and apparent volume of distribution was 12.9 L. The mean urinary excretion of unchanged drug over the 24-h period following the last dose was 36% of the dose while another 7% of the dose appeared in the urine as an acylglucuronide of zopolrestat. Renal clearance of zopolrestat was 1.82 ml min(minus sign1). Binding of zopolrestat to plasma proteins exceeded 99% and was concentration dependent.     

Pharmacokinetics of the novel cephalosporin cefepime (BMY-28142) in rats and monkeys.

The disposition of the novel cephalosporin cefepime (BMY-28142) was characterized for intravenous administration of single doses to rats and cynomolgus monkeys, the species used most extensively for safety evaluation of the compound. Serial blood samples were collected from individual animals, and plasma was analyzed for intact cefepime by a high-pressure liquid chromatography-UV method. Assay results were evaluated by compartmental and noncompartmental methods to characterize pharmacokinetics for each species and dosage regimen. For intravenous (i.v.) bolus administration of 28 to 386 mg/kg (body weight) to rats, total body clearance (CL; 11.0 ml/min per kg) was essentially invariant with the dose; however, the terminal half-life (t1/2) and the steady-state distribution volume (Vss) increased with increasing dose level. After administration of 87 to 1,502 mg/kg by i.v. infusion, CL (12.5 ml/min per kg) was again similar for all dose groups. Mean t1/2 values (1.3 to 4.6 h) appeared unusually long for a cephalosporin in rats, and inordinately variable. No consistent differences among dose group mean Vss values were found. The maximal concentration of drug in plasma at the end of infusion was not a linear function of dose. For the cynomolgus monkey, kinetic parameters for 5-min i.v. infusions were linearly related to dose over the range of 10 to 600 mg/kg. Mean parameter values were t1/2 = 1.7 h, CL = 1.6 ml/min per kg, and Vss = 0.21 liters/kg. The pharmacokinetic results indicate substantive differences between the two species with respect to their response to toxicologic doses of cefepime.     

Pharmacokinetics and burn eschar penetration of intravenous ciprofloxacin in patients with major thermal injuries

Adequate penetration of antibiotics into burn tissue and maintenance of effective serum levels are essential for the treatment of patients sustaining major thermal injuries. The pharmacokinetics and burn eschar penetration of intravenous ciprofloxacin were determined in 12 critically ill patients with burn injuries. Mean age for the 12 patients was 45 +/- 17 (range 25-82 years), total body surface area burned (TBSAB) = 38 +/- 15% and Acute Physiology and Chronic Health Evaluation (APACHE) II score = 8 +/- 6. Patients received recommended doses of ciprofloxacin, 400 mg q12h iv, for three doses beginning 72 h post-burn. Serum concentrations were measured at t = 0, 0.25, 0.5, 0.75, 1.0, 1.25, 1.5, 2.0, 4.0 and 12.0 h after the first and third doses. Burn eschar biopsies were obtained after the third ciprofloxacin dose. Three of these 12 patients (25%) manifested later signs of clinical sepsis (TBSAB = 61 +/- 6% and APACHE II score = 11 +/- 3) and underwent a second infusion of three doses of intravenous ciprofloxacin, blood sampling and eschar biopsy. Serum and eschar concentrations were determined by high performance liquid chromatography. Serum ciprofloxacin concentrations were comparable to those of normal volunteers (C(max) = 4.0 +/- 1 mg/L and AUC = 11.4 +/- 2 mg.h/L) during the immediate post-burn period after dose 1 (C(max1) = 4.8 +/- 3 mg/L and AUC(0-12) = 12.5 +/- 7 mg. h/L) and dose 3 (C(max3) = 4.9 +/- 2 mg/L and AUC(24-36) = 17.5 +/- 11 mg.h/L). Mean burn eschar concentration during the 72 h post-burn was significantly lower than that found during clinical sepsis (18 +/- 17 compared with 41.3 +/- 54 microg/g; P < 0.05 by t test). Similar serum concentrations were achieved in patients with clinical sepsis (C(max1) = 4.2 +/- 0.2 mg/L and AUC(0-12) = 15.0 +/- 3 mg. h/L; C(max3) = 5.0 +/- 1 mg/L and AUC(24-36) = 22.8 +/- 9 mg.h/L). A positive correlation between burn eschar concentrations and C(max) (r = 0.71, r(2) = 0.51, P = 0.01) was found by linear regression analysis. A C(max)/MIC ratio > 10 (MIC = 0.5 mg/L) and an AUC/MIC ratio > 100 SIT(-1).h (serum inhibitory titre) (MIC = 0.125 mg/L) were achieved. High burn eschar concentrations and serum levels, similar to those found in normal volunteers, can be achieved after intravenous ciprofloxacin infusion in critically ill burns patients.     

Pharmacokinetics of telbivudine following oral administration of escalating single and multiple doses in patients with chronic hepatitis B virus infection: pharmacodynamic implications

The pharmacokinetics of telbivudine were evaluated in adult patients with chronic hepatitis B virus (HBV) infection following once-daily oral administration at escalating doses of 25, 50, 100, 200, 400, and 800 mg/day for 4 weeks. Telbivudine was rapidly absorbed after oral administration, with the median times T(max) to the maximum plasma concentration (C(max)) ranging from 0.8 to 3.0 h postdosing across cohorts. Single-dose and steady-state maximum C(max)s and the areas under the plasma concentration-time curve from time zero to time t (AUC(0-t)s) increased proportionally with dose. At steady-state, the values of C(max) and AUC(0-t) were higher than those obtained after the administration of a single dose, indicative of a slight accumulation, with the ratios of the steady-state value to the value after the administration of a single dose ranging from 1.14 to 1.49 for C(max) and from 1.40 to 1.70 for AUC(0-t). While the elimination of telbivudine from plasma was apparently monophasic over the 8-h sampling period, the substantial steady-state trough plasma levels observed in the groups receiving doses of 100 to 800 mg were clearly indicative of the presence of a second slower elimination phase, with the mean estimated half-lives ranging from 29.5 to 41.3 h by compartmental modeling analysis. Pharmacokinetic and pharmacodynamic analyses by using maximum-effect modeling established a quantitative relationship between a reduction in serum HBV DNA levels and parameters of drug exposure, in particular, the steady-state C(max) and AUC(0-t). In summary, this study showed that telbivudine exhibits dose-proportional plasma pharmacokinetics with sustained steady-state drug exposure and exposure-related antiviral activity, supporting the need for further clinical studies by use of a once-daily regimen in patients with chronic HBV infection.     

Oral labetalol in hypertensive urgencies

The response to incremental doses of oral labetalol in 16 patients with hypertensive urgencies is presented. After inadequate blood pressure control with 20 mg of intravenous furosemide, each patient received a 300 mg oral dose of labetalol. Subsequent oral doses of labetalol, 100 mg, were administered at 2-hour intervals, if the diastolic blood pressure remained greater than 100 mm Hg. The maximum dose of labetalol per patient was 500 mg. Five patients required only the initial 300 mg dose of labetalol. Two patients required further therapy for satisfactory blood pressure control. Mean arterial pressure fell from 156 +/- 12 mm Hg to 123 +/- 14 mm Hg.     

Pharmacokinetics of clarithromycin, a new macrolide, after single ascending oral doses.

The pharmacokinetics and safety of single ascending doses of clarithromycin (6-0-methylerythromycin A) were assessed in a placebo-controlled, double-blind, randomized trial with 39 healthy male volunteers. Subjects were randomized to receive single doses of either placebo or 100, 200, 400, 600, 800, or 1,200 mg of clarithromycin. Blood and urine collections were performed over the 24 h following administration of the test preparation. Biological specimens were analyzed for clarithromycin and 14(R)-hydroxyclarithromycin content by a high-performance liquid chromatographic technique. The pharmacokinetics of clarithromycin appeared to be dose dependent, with terminal disposition half-life ranging from 2.3 to 6.0 h and mean +/- standard deviation area under the concentration-versus-time curve from time 0 to infinity for plasma ranging from 1.67 +/- 0.48 to 3.72 +/- 1.26 mg/liter.h per 100-mg dose over the 100- to 1,200-mg dose range. Similar dose dependency was noted in the pharmacokinetics of the 14(R)-hydroxy metabolite. Mean urinary excretion of clarithromycin and its 14(R)-hydroxy metabolite ranged from 11.5 to 17.5% and 5.3 to 8.8% of the administered dose, respectively. Urinary excretion data and plasma metabolite/parent compound concentration ratio data suggested that capacity-limited formation of the active metabolite may account, at least in part, for the nonlinear pharmacokinetics of clarithromycin. No substantive dose-related trend was observed for the renal clearance of either compound. There were no clinically significant drug-related alterations in laboratory and nonlaboratory safety parameters. In addition, there was no significant difference between placebo and clarithromycin recipients in the incidence or severity of adverse events. Clarithromycin appears to be safe and well tolerated.     

Pharmacokinetics of ciprofloxacin in liver cirrhosis

The pharmacokinetics of ciprofloxacin were evaluated in 11 patients (3 patients with impaired renal function) with advanced liver cirrhosis after a single oral dose of 500 mg. Mean serum peaks were 2.80 +/- 1.00 mg/l in 64 +/- 37 min after intake in patients with normal renal function. Elimination was reduced in comparison with healthy volunteers: t1/2 beta 510 +/- 158 min with a total area under the curve of 18.2 +/- 10.3 mg x h/l. Mean recovery of the parent compound from urine was 38 +/- 9% of the dose. In 3 patients with cirrhosis plus poor renal function, elimination was markedly reduced. In patients under 60 years with good renal function, the standard does not require a reduction.     

A dose ranging study of the pharmacokinetics, safety, and preliminary efficacy of lamivudine in children and adolescents with chronic hepatitis B

Fifty-three patients with chronic hepatitis B and active viral replication were studied for 4 weeks while on treatment and for 12 weeks after treatment with the oral nucleoside analogue lamivudine. Children aged 2 to 12 years were randomized to receive twice-daily doses of 0.35, 1.5, or 4 mg of lamivudine solution per kg of body weight or once-daily doses of 3 mg of lamivudine solution per kg. Adolescents aged 13 to 17 years received lamivudine at 100 mg (as tablets). Blood samples for pharmacokinetic assay were taken on days 1 and 28. Lamivudine was rapidly absorbed following oral administration, with the maximum concentration in serum being reached 0.5 to 1 h postdosing. Apparent oral clearance (CL/F) was higher in younger children and decreased with age, with CL/F values for adolescents reaching those seen for adults by the age of 12. All doses produced a dramatic fall in serum hepatitis B virus (HBV) DNA levels, with a median reduction of >/=99.5% after 4 weeks of treatment and with the levels returning to the baseline levels posttreatment. The correlation of dose, area under the concentration-time curve (AUC), and changes in HBV DNA levels, as measured by the Chiron Quantiplex assay, showed maximal antiviral effects (99.9% inhibition and a reduction of the amount of HBV DNA of approximately 3 log(10)) at 3 mg/kg/day, with no discernible increase in effect seen whether the drug was given at 4 mg/kg twice daily or whether it was given once daily or twice daily. The limit of detection of the assay (2.5 pg/ml) was reached for some but not all patients across the dose ranges, with the smallest number (n = 2) of those having values negative by the Chiron Quantiplex assay being in the lowest-dose group. The 13- to 17-year-olds showed a similar overall response in terms of the HBV DNA level reduction compared to that for patients younger than age 13. Analysis of the same samples by PCR, which has a lower limit of sensitivity than the Chiron Quantiplex assay, also showed average drops in HBV DNA levels of about 3 log(10) at 4 weeks for patients for which the AUC was >/=4,000 ng. h/ml, confirming the conclusions given above. Lamivudine treatment was well tolerated at all doses, with no significant adverse events or laboratory data changes. On the basis of pharmacokinetic and pharmacodynamic data, a 3-mg/kg/day dose in children (ages 2 to 12 years) with chronic hepatitis B provides levels of exposure and trough concentrations similar to those seen in adults following the receipt of doses of 100 mg. The 100-mg dose is being evaluated in a large phase III study with HBV-infected pediatric patients.     

Disposition kinetics and dynamics of nicainoprol, a new antiarrhythmic agent, in humans

Kinetics and resting and exercise-induced hemodynamic and ECG effects of nicainoprol, a new antiarrhythmic structurally resembling propafenone or propranolol, were investigated in eight healthy male subjects receiving a 1-hour infusion (100 mg) and oral dose (200 mg) in a randomized-crossover fashion. Nicainoprol in plasma and urine was determined by a specific HPLC assay. Plasma concentration-time data were fitted to a triexponential equation. Mean postinfusion kinetic data were: alpha-phase half-life = 3.1 minutes, beta-phase half-life = 106.6 minutes, and gamma-phase half-life = 12.4 hours; volume of central compartment = 0.114 L/kg; steady-state volume of distribution = 0.67 L/kg; total clearance = 3.6 ml/min/kg; and renal clearance = 0.56 ml/min/kg. Absolute bioavailability was approximately 70% and peak plasma drug concentration occurred 2.3 hours after oral administration. Interindividual variability in AUC was 1.6- and 2.4-fold after intravenous and oral administration, respectively. Cumulative fraction excreted unchanged in urine was approximately 15% and 9% of the dose after intravenous and oral administration, respectively. Resting heart rates were increased, whereas exercise-induced heart rates were unchanged after both doses. QRS durations were widened after both doses. PR and QTc intervals were prolonged during intravenous study. The results suggest that nicainoprol is an enzyme-limited or poorly extracted drug suitable for both intravenous and oral administration and devoid of beta-blocking action in humans, at least with doses tested in this study. Its ECG properties appear to be similar to those of class I antiarrhythmics.     

Amphotericin B dose optimization in children with malignant diseases

In this study, rational dosing guidelines for amphotericin B-deoxycholate (AmB) are proposed for children. AmB steady-state trough concentrations (C(ss,trough)) and plasma creatinine concentrations (C(creat)) were measured in 83 children (age: 10 months to 18 years) receiving prophylactic AmB therapy (1 mg/kg/day). Maximum tolerable AmB C(ss,trough) were identified by determining the probability of large (>24%, 75th percentile) increases in C(creat) after 6 days of AmB for a series of C(ss,trough) ranges. Dose requirements were determined using a concentration-targeting approach. The 0.76-1.05 mg/l C(ss,trough) range provided the maximum concentrations that still had a low probability (p < 0.29) of adverse renal effects. 1 mg/kg/day AmB produces C(ss,trough) within this range for children weighing 25-45 kg. Lighter children (10-25 kg) require higher AmB doses (1.25-1.5 mg/kg/day) to achieve target C(ss,trough), while heavier children (45-55 kg) require lower doses (0.75 mg/kg/day). These starting dose guidelines may require individualization and prospective evaluation.     

Nilotinib for imatinib-resistant or -intolerant chronic myeloid leukemia in chronic phase,accelerated phase,or blast crisis: A single- and multiple-dose,open-label pharmacokinetic study in Chinese patients

Background: Nilotinib, an oral second-generation Bcr-Abi tyrosine kinase inhibitor, is approved in the United States and European Union for the treatment of Philadelphia chromosome-positive (Ph+), chronic-phase (CP) or accelerated-phase (AP) chronic myeloid leukemia (CML) resistant to or intolerant of prior therapy, including imatinib. Information on the pharmacokinetics of nilotinib in Chinese patients with CML is lacking, and regulatory requirements for registration of this drug are needed in China.Objectives: This study assessed the pharmacokinet-ics of single and multiple oral doses of nilotinib in Chinese patients with CML and compared the pharmacokinetic profiles of nilotinib between the Chinese patients and a subgroup of white patients with CML.Methods: Chinese patients aged ≥18 years with Ph+ CML-CP, CML-AP, or CML-BC (blast crisis) resistant to or intolerant of imatinib were eligible. Patients were administered oral nilotinib 400 mg BID for 15 days. Serial blood samples were collected before and at 1, 2, 3, 5, 8, and 12 hours after the administration of a single dose (day 1) and multiple doses (day 15, steady state). Serum nilotinib concentrations were determined using a validated liquid chromatography-tandem mass spectrometry assay, and pharmacokinetic parameters of nilotinib were calculated using a noncompartmental method. Tolerability was assessed using cardiac assessments; laboratory analysis (hematology, blood chemistry, and urinalysis); and physical examination, including vital signs.Results: Twenty-three patients were enrolled (18 men, 5 women; mean age, 40.0 years; mean weight, 68.3 kg; CML-CP, 22 patients; CML-AP, 1). All 23 patients were included in the tolerability analysis. Two patients withdrew consent and discontinued after administration of the first dose; thus, 21 patients were included in the pharmacokinetic analysis. Median T^max was ~2 hours after administration of single and multiple doses. At steady state, C_min was 1025.4 ng/mL and C_max was 2160.7 ng/mL. Mean AUCs from time 0 to the end of the dosing interval τ (AUC_0-τ) were 5076.3 and 17,751.3 ng · h/mL at days 1 and 15, respectively, representing an accumulation factor of 3.92. Apparent oral clearance (CL/F) was 0.39 L/h/kg (range, 0.12–0.74 L/h/ kg) at steady state. The study found a 42% intersubject variability in nilotinib pharmacokinetics. Steady-state C_max, C_min, AUC_0-τ, and CL/F were not significantly different from those previously reported in a subgroup of white patients with CML who received the same 400-mg BID dose. Rash (11/23 patients [47.8%]) and elevated bilirubin, headache, and muscle pain (4 patients each [17.4%]) were the most frequently reported nonhematologic adverse events.Conclusions: In this pharmacokinetic study in Chinese patients with CML resistant to or intolerant of imatinib, nilotinib 400 mg BID was rapidly absorbed after a single dose and multiple doses. The steady-state pharmacokinetic properties in this population were consistent with those reported previously in white patients with CML.     

Pharmacokinetic-pharmacodynamic analysis of drotrecogin alfa (activated) in patients with severe sepsis

OBJECTIVE: We aimed to characterize the pharmacokinetics and pharmacodynamics of drotrecogin alfa (activated) (recombinant human activated protein C) in patients with severe sepsis. METHODS: Patients (N = 1690) in a randomized, double-blind, placebo-controlled phase 3 trial received a 96-hour infusion of placebo (n = 840) or drotrecogin alfa (activated) (n = 850), 24 microg x kg(-1) x h(-1). Plasma samples from 680 patients were collected for pharmacokinetic assessment. Pharmacodynamic effects on activated partial thromboplastin time, D-dimer, protein C, and interleukin 6 were analyzed by drotrecogin alfa (activated) steady-state plasma concentration (C(ss)) quartile. RESULTS: Transient endogenous activated protein C concentrations above 10 ng/mL were observed in 11 placebo-treated patients (3.3%). In drotrecogin alfa (activated)-treated patients, the median C(ss) was 44.9 ng/mL and the median plasma clearance (CL(p)) was 40.1 L/h. C(ss) was reached within 2 hours after the infusion was started. Plasma concentrations were below the assay quantitation limit of 10 ng/mL within 2 hours after the infusion was stopped in 92% of patients. CL(p) increased with increasing body weight, so infusion rates should be based on predose body weight. Mean CL(p) associated with age, sex, or baseline hepatic or renal function differed by less than 30% from the mean CL(p) in all patients and resided within the interquartile range of CL(p) in all patients. Dose adjustment is not required on the basis of these factors alone or in combination. No correlation was detected between C(ss) quartile and bleeding risk or the magnitudes of effect on biomarkers of coagulopathy (D-dimers and protein C) and inflammation (interleukin 6). CONCLUSIONS: Plasma concentrations of drotrecogin alfa (activated) attain steady state rapidly after the infusion is started and decline rapidly after the infusion is stopped. The infusion rate should be based on predose body weight and not on any other demographic or baseline clinical covariate.     

Pharmacokinetic Study of Human Immunodeficiency Virus Protease Inhibitors Used in Combination with Amprenavir

In an open-label, randomized, multicenter, multiple-dose pharmacokinetic study, we determined the steady-state pharmacokinetics of amprenavir with and without coadministration of indinavir, nelfinavir, or saquinavir soft gel formulation in 31 human immunodeficiency virus type 1-infected subjects. The results indicated that amprenavir plasma concentrations were decreased by saquinavir soft gel capsule (by 32% for area under the concentration-time curve at steady state [AUC(ss)] and 37% for peak plasma concentration at steady state [C(max,ss)]) and increased by indinavir (33% for AUC(ss)). Nelfinavir significantly increased amprenavir minimum drug concentration at steady state (by 189%) but did not affect amprenavir AUC(ss) or C(max,ss). Nelfinavir and saquinavir steady-state pharmacokinetics were unchanged by coadministration with amprenavir compared with the historical monotherapy data. Concentrations of indinavir, coadministered with amprenavir, in plasma decreased in both single-dose and steady-state evaluations. The changes in amprenavir steady-state pharmacokinetic parameters, relative to those for amprenavir alone, were not consistent among protease inhibitors, nor were the changes consistent with potential interactions in CYP3A4 metabolism or P-glycoprotein transport. No dose adjustment of either protease inhibitor in any of the combinations studied is needed.     

Pharmacokinetic and pharmacodynamic study of the human immunodeficiency virus protease inhibitor amprenavir after multiple oral dosing

In a dose-ranging study of amprenavir (formerly 141W94), an inhibitor of the protease enzyme of human immunodeficiency virus (HIV) type 1, single-dose and steady-state pharmacokinetic parameters were estimated from plasma samples collected on day 1 and during week 3, respectively. Amprenavir was administered on either a twice-daily (b.i.d.) or three-times-daily dosage schedule to 62 HIV-infected adults, 59 of whom had pharmacokinetic data. Log-log regression analysis (the power model) revealed that the steady-state area under the curve (AUC(ss)) and the maximum, minimum, and average concentrations at steady state (C(max,ss), C(min,ss), and C(avg,ss), respectively) increased in a dose-proportional manner over the 300- to 1,200-mg dose range. Steady-state clearance was dose independent. AUC(ss)/AUC(0-->infinity) decreased linearly with dose and correlated significantly with treatment-associated decreases in alpha(1)-acid glycoprotein. After 3 weeks, the dose of 1,200 mg b.i. d. provided a median amprenavir C(min,ss) (0.280 microg/ml) that was higher than the median in vitro 50% inhibitory concentration for clinical HIV isolates (0.023 microg/ml), even after adjustment for protein binding. The median amprenavir C(min,ss) was also greater than the estimated in vivo trough concentration calculated to yield 90% of the maximum antiviral effect (0.228 microg/ml) over 4 weeks. A pharmacodynamic analysis of the relationship between steady-state pharmacokinetic parameters and safety revealed headache and oral numbness to be the only side effects significantly associated with C(max). The pharmacodynamic relationship defined in this study supports the use of 1,200 mg b.i.d. as the approved dose of amprenavir.     

Lorcainide disposition kinetics in arrhythmia patients

Lorcainide disposition kinetics were studied after intravenous and oral administration to patients with ventricular arrhythmias. After intravenous doses ranging from 100 to 200 mg, blood samples were drawn and plasma was analyzed for lorcainide concentration by high-pressure liquid chromatography. A three-compartment model was used to fit the data. The model-independent calculated values for clearance, steady-state volume of distribution, and terminal half-life were 14.4 +/- 3.28 ml/min/kg, 6.33 +/- 2.23 l/kg, and 7.8 +/- 2.2 hr. After nine doses of oral lorcainide (100 mg every 12 hr) blood samples were drawn and analyzed for lorcainide and its active metabolite, norlorcainide. The lorcainide and norlorcainide half-lifes were 9.6 +/- 2.8 and 26.8 +/- 8.2 hr. Mean steady-state level of norlorcainide was 2.2 +/- 0.9 times the level of lorcainide. The data suggest that the clearance of lorcainide decreases with time during long-term dosing.