Linear single-dose pharmacokinetics of ganciclovir in newborns with congenital cytomegalovirus infections. NIAID Collaborative Antiviral Study Group.

The pharmacokinetic characteristics of ganciclovir were determined in neonates (age range, 2 to 49 days) after an 1-hour intravenous infusion of a single dose of either 4 mg/kg (n = 14) or 6 mg/kg (n = 13). Twenty-seven newborns with symptomatic cytomegalovirus inclusion disease were enrolled in this open phase I-II pharmacokinetics, safety, and tolerance trial of ganciclovir at one of two doses. Ganciclovir disposition was best described by a one-compartment open model with zero-order input and first-order elimination. The mean elimination half-life (t1/2) for both dose groups was 2.4 hours. The mean apparent volume of distribution (Vd) was 669 +/- 70 ml/kg for the 4 mg/kg group and 749 +/- 59 ml/kg for the 6 mg/kg group. The mean total body clearance (CL) for the 4 mg/kg and 6 mg/kg groups was 189 +/- 28 ml/hr/kg and 213 +/- 21 ml/hr/kg, respectively. No significant differences were observed in Vd or CL between the two groups. The Vd, expressed in milliliters, increased with increasing patient weight (r = 0.689; p = 0.0001). The CL, expressed in milliliters per hour per kilogram, increased with increasing age (r = 0.413; p = 0.032). No significant differences were observed between the two dose groups for the area under the curve normalized for dose (AUC/Dose) or the maximum plasma concentration normalized for dose (Cmax/Dose), indicating that ganciclovir exhibited linear pharmacokinetics in these neonates.

The effect of vitamin C on the pharmacokinetics of caffeine in elderly men.

The influence of vitamin C on the pharmacokinetics of caffeine was investigated in 10 elderly males, age 66 to 86 yr. Caffeine was administered intravenously on three different occasions over a 7-wk period: before vitamin C restriction, after approximately 4 wk of vitamin C restriction (15 mg dietary intake per day), and after 2 wk of vitamin C supplementation (500 mg orally, twice daily). Blood and urine samples were collected over a 48-h period after each caffeine administration. The plasma half-life, rate constant of elimination, apparent volume of distribution, total body clearance, renal clearance, and metabolic clearance of caffeine were determined. Simultaneous plasma, whole blood and leukocyte vitamin C concentrations were obtained. All of the average vitamin C concentrations monitored (plasma, whole blood, and leukocyte) changed significantly during the study, corresponding to the alterations in dietary vitamin C intake. Conversely, none of the caffeine pharmacokinetic parameters evaluated changed significantly during the study. The average metabolic clearance was approximately 77 (ml hr-1) kg-1 and the average half-life was approximately 4.6 h for all caffeine administrations. These results indicate that the elimination of caffeine in the elderly is not affected significantly by the concentrations of vitamin C achieved during this study.

Cardiovascular effects of caffeine in elderly men.

Ten healthy elderly male volunteers were given 4 mg/kg of caffeine by intravenous infusion on three separate occasions. This resulted in mean peak plasma concentrations of caffeine of 7.4 +/- 0.7 micrograms/ml. Immediately after each of the three caffeine infusions, the mean systolic blood pressures increased 14, 7, and 16 mm Hg, and the mean diastolic blood pressures increased 7, 4, and 7 mm Hg, respectively. Both the systolic and the diastolic blood pressures returned to preinfusion values within 4 hours. The QS2 index and the left ventricular ejection time (LVET) index increased after caffeine, probably as a result of the caffeine-induced increase in arterial blood pressure. The pre-ejection period (PEP), the PEP/LVET ratio, and the diastolic time remained unchanged. Caffeine, in doses equal to those contained in 2 to 3 cups of coffee, produces an increase in blood pressure but has no demonstrable positive inotropic effect in healthy elderly men.

Bioavailability of digoxin tablets in healthy volunteers.

The bioavailability of digoxin generic tablets manufactured in Korea (formulations A & B) were compared to a standard (formulation C; Lanoxin brand digoxin, Burroughs Wellcome, USA) in 12 healthy Korean male volunteers (mean age 31.4 years) in a single dose, randomized, complete block crossover study. Using a Latin square design, each of the subjects was randomized to the order number and allocated to each of the three treatments of 0.5 mg oral digoxin. Digoxin concentrations in serum and urine samples collected for 48 hours after dosing were measured by fluorescence polarization immunoassay and radioimmunoassay, respectively. Treatments were compared by using nonlinear least squares regression analysis to evaluate the following pharmacokinetic parameters: maximum serum concentration (Cmax); time of maximum serum concentration (Tmax); area under the serum concentration-time curve for 0-12 hours (AUC0-12); and cummulative urinary excretion for 0-48 hours (CUE0-48). Mean AUC0-12, Cmax, and CUE0-48 values for formulations B and C were significantly different from formulation A (p < 0.001), but not significantly different from each other. Based on AUC0-12 and CUE0-48, respectively, the relative availability of formulation B was 87.5% and 89.6% and the relative availability of formulation A was 43% and 35% when compared to formulation C (the standard).

Pharmacokinetics of CPX-351; a nano-scale liposomal fixed molar ratio formulation of cytarabine:daunorubicin, in patients with advanced leukemia.

Forty-eight patients received CPX-351 (liposome-encapsulated cytarabine:daunorubicin at a 5:1 molar ratio) every other day for 3 doses at 10 dose levels. Pharmacokinetic parameters were dose-independent and exhibited low inter-patient variability. CPX-351 showed a negligible distribution phase and prolonged mono-exponential first-order plasma elimination (t(1/2)∼24 h). The plasma ratio of 5:1 was maintained at all dose levels. Nearly all of the detectable cytarabine and daunorubicin in circulation following CPX-351 administration was in the form of liposome encapsulated drug. Dose-dependent hematopoietic effects had early onset with cytopenias at 12 units/m(2), and a gradual increase in frequency and severity, until single induction complete response was achieved at 43 units/m(2). Non-hematologic effects had onset by 24 units/m(2) with shallow dose-response until maximum frequency and severity were observed at the 101-134 units/m(2) dose levels. Single induction response occurred over a 2.3-fold range of doses indicating that CPX-351 may be useful at high doses for patients suitable for intensive chemotherapy and at reduced doses for patients at increased risk of treatment-related mortality. The unique pharmacologic features of CPX-351 contribute to its promising antileukemic efficacy.

Introduction to pharmacokinetics: aminoglycosides in cystic fibrosis as a prototype.

Pharmacokinetics is the study of the time course of drug absorption, distribution, metabolism, and excretion, allowing examination of the potential relationships between drug disposition and pharmacologic or toxicologic effects. The pharmacokinetics of the aminoglycosides and certain other drugs are different in patients with cystic fibrosis (CF), but this topic is controversial. Differences in disease severity between study subjects and in the methods used might explain the disparities. Understanding the fundamental principles of pharmacokinetics is necessary for the clinician to evaluate drug disposition data in patients with CF. To determine whether observed pharmacokinetic differences are attributable to CF, the investigator must consider a number of factors in the design and conduct of pharmacokinetic studies: analytical methods, study population selection, techniques for drug administration, method used to collect biologic specimens, evaluation of parallel rates and routes of drug excretion, and selection of pharmacokinetic and statistical techniques. Pharmacokinetic investigation in patients with CF should permit evaluation of the complete disposition profile for a drug, allow comparison between the experimental data and factors that characterize the disease state, and be rigorous enough to provide explanations for any observed variability in pharmacokinetics.

Stability of cefotaxime sodium and metronidazole in an i.v. admixture at 8 degrees C.

The stability of cefotaxime and metronidazole in i.v. admixture at 8 degrees C was studied. The commercially available injectable formulation of cefotaxime sodium 1 g was diluted to 5 mL with 0.9% sodium chloride injection and added to metronidazole injection 500 mg/100 mL. A 2-mL sample was removed and diluted to 100 mL with water. Thirty 1-mL portions were transferred to glass vials and refrigerated at 8 degrees C. At 0, 1, 2, 4, 8, 12, 24, 36, 48, and 72 hours after the admixture was prepared, the vials were removed, placed in a refrigerated autosampler, and assayed for cefotaxime and metronidazole concentrations by stability-indicating high-performance liquid chromatography. Over the 72-hour study period, the concentration of cefotaxime remaining at all assay times was 95.91-101.13% of the initial concentration. The concentration of metronidazole remaining at each assay time was 93.08-102.19% of the initial concentration. Cefotaxime sodium 10 mg/mL and metronidazole 5 mg/mL were stable for 72 hours at 8 degrees C in an i.v. admixture prepared from commercially available injectable formulations.

Stability of cefazolin sodium and metronidazole at 8 degrees C for use as an i.v. admixture.

The stability of cefazolin 1 g in metronidazole 500 mg/100 mL at 8 degrees C was studied for use as an IV admixture. The commercially available injection of cefazolin sodium 1 g vial was diluted to 5 mL with 0.9% sodium chloride injection and added to metronidazole 500 mg/100 mL. Following dilution of 2 mL to 100 mL with water, 1-mL aliquots were transferred to glass vials, refrigerated at 8 degrees, and assayed for cefazolin and metronidazole concentration at 0, 1, 2, 4, 8, 12, 24, 36, 48, and 72 hours after preparation. The concentration of cefazolin and metronidazole was determined by a stability-indicating high-performance liquid chromatographic method. The range of concentration was determined to be within 5% of the 0-hour mean concentration. Over the 72-hour period, the mean concentration of cefazolin at all assay times was within 98.4 to 101.0% of the initial concentration. The mean concentration of metronidazole at each assay time was 96.9 to 104.9% of the initial concentration. Cefazolin sodium 10 mg/mL and metronidazole 5 mg/mL, prepared by adding reconstituted cefazolin to a glass bottle of metronidazole ready-to-use solution, were stable for 72 hours when stored at 8 degrees C.

Relationship between total body clearance of caffeine and urine flow rate in elderly men.

The total body clearance (CL), renal clearance (CLR), and nonrenal clearance (CLNR) of caffeine from plasma were determined following the intravenous administration of caffeine (4 mg kg-1) to ten healthy men (aged 66-86 years) on three separate occasions. Positive correlations were observed between CL and urine flow rate (UFR), between CLR and UFR, and between CLNR and UFR (r = 0.8947, p = 0.0002; r = 0.8832, p = 0.0003; and r = 0.8920, p = 0.0002, respectively). Previous studies have established similar relationships between CLR and UFR for caffeine and its initial dimethylxanthine metabolites; theophylline, theobromine, and paraxanthine. A relationship between CL and UFR has not been reported previously.

Stability of gentamicin sulfate and tobramycin sulfate in extemporaneously prepared ophthalmic solutions at 8 degrees C.

The stability of gentamicin sulfate and tobramycin sulfate in fortified ophthalmic solutions stored under refrigeration was studied. Fortified gentamicin ophthalmic solution and fortified tobramycin ophthalmic solution were prepared to a final theoretical concentration of 13.6 mg/mL by using commercially available ophthalmic and injectable solutions. Volumes of each solution were packaged in plastic bottles and refrigerated at 4-8 degrees C. Samples of each solution were analyzed by fluorescence polarization immunoassay on days 0 (before refrigeration), 1, 2, 3, 4, 7, 14, 28, 63, and 91. To validate the method, identical solutions were prepared, stored under refrigeration at 4-8 degrees C, and analyzed by a stability-indicating high-performance liquid chromatographic assay on days 0 (before refrigeration), 9, 28, 56, and 91. Fluorescence polarization immunoassay showed the mean concentrations of gentamicin and tobramycin on day 91 to be 104.4% and 97.4%, respectively, of the time 0 concentrations; the difference was not significant in either case. HPLC validated these results; the mean concentration of gentamicin and tobramycin on day 91 was 103.3% and 101.2%, respectively, of the mean day 0 concentrations. Gentamicin and tobramycin in ophthalmic solutions prepared by mixing ophthalmic and injectable products and stored in plastic bottles at 4-8 degrees C were stable for three months.

Disposition of cefonicid in orthopedic surgery patients.

Ten patients undergoing hip reconstructive procedures were given a single prophylactic dose of cefonicid 15 mg/kg to evaluate intraoperative and perioperative drug disposition in the surgical setting. Timed postinfusion serum samples were collected over 24 hours and resulting concentration versus time data were subjected to noncompartmental pharmacokinetic analysis. Bone samples were obtained in eight of ten patients with mean bone concentrations of 13.3 micrograms/g (range 8.2-25.1). Postinfusion serum concentrations at five minutes postinfusion ranged from 200.8 to 316.7 micrograms/ml; the 12-hour mean was 19.1 micrograms/ml (range 4.0-48) and the 24-hour mean was 4.3 micrograms/ml (range 0.0-13.8). Protein binding at three sampling times ranged from 88 to 96.5 percent, increasing over time as total cefonicid concentrations fell. The mean half-life in our patients was 3.5 hours, compared with 4.8 hours in our four controls. These data indicate that altered protein binding and intraoperative events alter the disposition of cefonicid. Although differences in disposition parameters between patients and controls were not statistically significant, suboptimal serum cefonicid concentrations were observed in four orthopedic patients.

Zidovudine bioavailability and linear pharmacokinetics in female B6C3F1 mice.

The bioavailability and pharmacokinetics of zidovudine (3'-azido-3'-deoxythymidine) (AZT) were determined in female B6C3F1 mice after administration of 15, 30, and 60 mg/kg doses via oral gavage or intravenous injection. Three animals in each administration group were sacrificed, and blood samples were collected at each of the following times: 0, 5, 10, 15, 20, 30, 45, 60, 75, 90, 105, and 120 min after drug administration. Plasma zidovudine concentrations were determined by HPLC. After oral administration, mean maximum plasma concentrations (Cmax) of 9.1, 18.9, and 40.3 mg/liter were observed at 18.3, 21.7, and 15.0 min (tmax) for the 15, 30, and 60 mg/kg doses, respectively. Following intravenous administration, mean Cmax values of 15.9, 41.8, and 76.0 mg/liter were observed for the 15, 30, and 60 mg/kg doses, respectively. Nonlinear least squares regression of all data sets, using a 1/y weight, indicated that zidovudine disposition was best described by a one-compartment open model with first-order absorption, where appropriate, and first-order elimination. The mean elimination half-life values ranged from 17.3 to 19.9 min for the three intravenous doses and from 16.5 to 21.9 min for the three oral doses. The mean values for the apparent volume of distribution (Vd) ranged from 0.8 to 1.0 liter/kg following oral and intravenous administration. There were no significant differences in Vd between the oral and intravenous groups. The mean total body clearance values ranged from 28.9 to 34.3 ml/min/kg following intravenous administration.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of age and renal function on cefonicid pharmacokinetics.

Cefonicid (15 mg/kg) was administered intravenously at a constant rate of infusion over 15 min to 10 geriatric patients (mean age, 77 years) and to 4 young subjects (mean age, 35 years). Model-dependent and noncompartmental pharmacokinetic parameters were calculated and found to be congruous; noncompartmental data are reported. Significant differences in the values for area under the curve, mean residence time, total body clearance, and renal clearance were observed between the geriatric and young groups. Mean elimination half-life values were 9.59 and 4.88 h for the geriatric and young groups, respectively. Total body and renal clearances were inversely correlated to age and directly correlated to creatinine clearance. Free fraction was not correlated to albumin concentration but was correlated exponentially to total cefonicid concentration. Despite the prolonged half-life values observed in our geriatric patients, the difference in mean trough concentrations was slight. Daily administration of a 15-mg/kg dose should provide adequate concentrations in serum and should not produce appreciable accumulation in geriatric patients.

Cefotaxime therapy of bacterial meningitis in children.

Thirty children with bacterial meningitis were randomized to receive either ampicillin and chloramphenicol in standard doses or cefotaxime (50 mg/kg/dose every 6 h) for 10 to 14 days. Eighteen patients received ampicillin and chloramphenicol and 12 patients received cefotaxime. Cerebrospinal fluid isolated included: Haemophilus influenzae (20), Streptococcus pneumoniae (4), Neisseria meningitidis (3), Group B streptococcus (2), and Salmonella enteritidis (1). Five of the H. influenzae isolates were ampicillin resistant but no isolates were resistant to cefotaxime. The minimum inhibitory concentrations of cefotaxime for 30 isolates ranged from 0.0004 to 0.06 mg/l, while the minimum bactericidal concentrations ranged from 0.007 to 0.12 mg/l. The cerebrospinal fluid bactericidal titres for the cefotaxime-treated group ranged from 1:64 to 1:1024. On the second day of therapy the mean cefotaxime serum concentrations were 56.9 +/- 28.7 mg/l at 1 h and 3.66 +/- 5.65 mg/l at 6 h after administration of the drug whilst mean desacetyl-cefotaxime serum concentrations were 12.31 +/- 7.56 mg/l at one hour and 7.96 +/- 8.26 mg/l at 6 h respectively. Cerebrospinal fluid concentrations of cefotaxime and desacetylcefotaxime measured one hour after drug administration were 3.72 +/- 5.57 mg/l and 4.35 +/- 7.12 mg/l, respectively. No adverse drug reactions were noted in either treatment group. Cefotaxime proved to be both as safe and as efficacious as standard therapy for the treatment of bacterial meningitis in children.

Renal clearance of imipenem in children.

Imipenem renal clearance was studied in six children (three males, three females; 2.9-11.2 years of age) following a single intravenous dose (21.7 +/- 5.1 mg/kg) of imipenem/cilastatin (1:1). In an approximately six-hour period following drug administration, 65.3 +/- 9.7% of the imipenem dose was excreted in the urine unchanged. The renal clearance (280.03 +/- 24.34 ml/min/1.73 m2) of imipenem was found to account for 69.2% of the corresponding plasma imipenem clearance (404.89 +/- 24.83 ml/min/1.73 m2). Contrary to existing adult data, the imipenem renal clearance in our subjects was 1.95-fold greater than the estimated creatinine clearance, suggesting significant tubular secretion of imipenem in children. Examination of urinary imipenem excretion rate versus plasma concentration relationships in three of the children revealed a potential renal tubular reabsorption component for imipenem in children. Comparison of renal imipenem clearance data in these children to similar data from adults suggests that quantitatively important developmental differences may exist for the renal handling of imipenem.

Cefotaxime and desacetylcefotaxime pharmacokinetics in very low birth weight neonates.

The single-dose pharmacokinetics of cefotaxime (CTX) and desacetylcefotaxime (dCTX) after a 50.0 mg/kg intravenous dose were evaluated in 18 very low birth weight neonates (13 male; 1015.6 +/- 349.8 gm; 28.4 +/- 2.4 weeks gestational age) during the first week of life. Microanalytic high-performance liquid chromatography was used to quantitate both CTX and dCTX from serum. A two-compartment open model best characterized the disposition of CTX during a 24-hour post-dose period. The disposition of dCTX was adequately characterized by a one-compartment model. The elimination half-life, apparent steady-state volume of distribution, and total body clearance of CTX (mean +/- SEM) were 4.44 hours, 0.461 +/- 0.027 L/kg, and 0.074 +/- 0.003 L/hr/kg, respectively. Peak concentrations (mean +/- SD) of dCTX (17.96 +/- 5.54 mg/L) occurred at 0.6 to 8.3 hours (5.9 +/- 1.9 hours) after CTX administration, and the apparent elimination half-life of dCTX was 9.36 hours. Comparison of CTX and dCTX pharmacokinetic parameters between very low birth weight neonates who weighed less than 1000 gm (n = 9; 703.3 +/- 46.6 gm; 27.0 +/- 0.8 weeks gestational age) and greater than or equal to 1000 gm (n = 9; 1328.8 +/- 48.6 gm; 29.8 +/- 0.5 weeks gestational age) revealed no significant differences, but significant linear correlations were found between gestational age and weight versus CTX half-life and total body clearance. Because of the prolonged clearance of both CTX and dCTX in the very low birth weight neonate, a CTX dose of 50 mg/kg every 24 hours may provide effective serum concentrations for susceptible infections outside the central nervous system.

Rapid estimation of serum theophylline clearance in children with acute asthma.

Serum theophylline clearance was estimated prior to reaching steady state in 29 asthmatic children, aged 1-14 years, using methods described by Chiou et al. and Vozeh et al. Comparison of the estimated clearance by the Vozeh method (0.094 +/- 0.005 L/kg/h) did not differ significantly from that estimated by the Chiou method (0.094 +/- 0.005 L/kg/h). Neither estimate of serum theophylline clearance differed significantly from the calculated clearance at steady state (0.092 +/- 0.006 L/kg/h). Linear correlations between predicted and observed serum theophylline clearances were found for both the Chiou (p = 0.002, r = 0.54) and Vozeh (p = 0.02, r = 0.49) methods. Estimates of the steady-state serum theophylline concentrations by the Vozeh method (10.32 +/- 0.56 mg/L) and the Chiou method (10.28 +/- 0.52 mg/L) did not differ significantly from each other or from the observed steady-state serum theophylline concentration (10.54 +/- 0.48 mg/L). A linear correlation between predicted and observed serum theophylline concentrations was found for both the Chiou (p = 0.02, r = 0.43) and Vozeh (p = 0.001, r = 0.57) methods. These results suggest that either method of estimating serum theophylline clearance can be used to rapidly individualize therapy in children with acute asthma.

Single-dose pharmacokinetics of imipenem in children.

The single-dose pharmacokinetics of imipenem (N-formimidoyl thienamycin) was evaluated in 13 pediatric patients (mean age 5.2 +/- 3.5 years). Imipenem was administered in combination with cilastatin as either a 10 mg/kg or 25 mg/kg dose (not to exceed 500 mg) over 15 minutes. Plasma disposition in children was best described by a two-compartment open model. The distribution phase was rapid (t1/2 lambda 1 = 0.18 hours) and was followed by a monoexponential elimination phase (t1/2 lambda 2 = 1.2 hours). The calculated value for the apparent volume of distribution (0.66 L/kg) was similar to that of total body water. The total plasma clearance was rapid (0.36 L/hr/kg). Direct proportionality was exhibited between administered dose and either resultant plasma concentration or area under the plasma concentration versus time curve. Comparison of imipenem plasma pharmacokinetic data derived from these children with data reported from adult subjects revealed disparities for both the apparent volume of distribution and plasma clearance. Based on preliminary pharmacokinetic simulations using parameters generated from our study, a 25.0 mg/kg dose of imipenem administered every 6 hours appears adequate for initiation of therapy in children.

Pharmacokinetics of a mouse/human chimeric monoclonal antibody (C-17-1A) in metastatic adenocarcinoma patients.

The pharmacokinetic characteristics of a mouse/human chimeric monoclonal antibody (C-17-1A) were determined in 10 patients with metastatic adenocarcinoma following the administration of either 10-mg or 40-mg infusions as a single or multiple dose. The administration of single 10-mg (n = 5) and 40-mg (n = 5) doses infused over 1 hr resulted in mean apparent steady-state distribution volumes of 4.13 +/- 0.97 and 5.16 +/- 1.92 liters, respectively, indicating that C-17-1A appears to distribute throughout the vascular compartment and into limited extracellular fluid volume. The disposition of C-17-1A was adequately characterized using a two-compartment open model with mean distribution half-lives of 15.8 and 18.5 hr and mean elimination half-lives of 90.0 and 97.6 hr for the 10- and 40-mg groups, respectively. A linear relationship was observed between AUC and dose (micrograms/kg). The clearance of C-17-1A was correlated linearly with total Ig, IgG, and tumor size. Multiple administration of either 10-mg (n = 3) or 40-mg (n = 3) doses of C-17-1A infused over 1 hr every 14 days for a total of three doses resulted in superimposable mean serum concentration versus time data and consistent mean pharmacokinetic characteristics. These data indicate that C-17-1A exhibits linear, nonsaturable distribution and elimination characteristics in man over the dose range studied (i.e., 130 to 880 micrograms/kg). The multiple-dose pharmacokinetics of C-17-1A were predictable, indicating a lack of an antibody response to C-17-1A over a period of 42 days.(ABSTRACT TRUNCATED AT 250 WORDS)