Clinical Pharmacokinetics of 1-[((S)-2-Hydroxy-2-Oxo-1,4,2-Dioxaphosphorinan-5-yl)methyl]cytosine in Human Immunodeficiency Virus-Infected Patients

The pharmacokinetics and bioavailability of 1-[((S)-2-hydroxy-2-oxo-1,4,2-dioxaphosphorinan-5-yl)methyl]cytosine (cyclic HPMPC) were examined at four doses in 22 patients with human immunodeficiency virus infection. Two groups of six patients received a single dose of cyclic HPMPC at 1.5 or 3.0 mg/kg of body weight by each of the oral and intravenous routes in a random order with a 2-week washout period between administrations. Additional patients received single intravenous doses of cyclic HPMPC at 5.0 mg/kg (n = 6) or 7.5 mg/kg (n = 4). Serial serum and urine samples were collected at intervals over 24 h after dosing. The concentrations of cyclic HPMPC and cidofovir in serum and urine samples were determined by validated reverse-phase ion-pairing high-performance liquid chromatography methods with derivatization and fluorescence detection. After intravenous administration of cyclic HPMPC, concentrations of cyclic HPMPC declined in a biexponential manner, with a mean ± standard deviation half-life of 1.09 ± 0.12 h (n = 22). The pharmacokinetics of cyclic HPMPC were independent of dose over the dose range of 1.5 to 7.5 mg/kg. The total clearance of cyclic HPMPC from serum and the volume of distribution of intravenous cyclic HPMPC were 198 ± 39.6 ml/h/kg and 338 ± 65.1 ml/kg, respectively (n = 22). The renal clearance of cyclic HPMPC (132 ± 27.3 ml/h/kg; n = 22) exceeded the creatinine clearance (86.2 ± 16.3 ml/h/kg), indicating active tubular secretion. The cyclic HPMPC excreted in urine in 24 h accounted for 71.3% ± 16.0% of the administered dose. Cidofovir was formed from cyclic HPMPC in vivo with a time to the maximum concentration in serum of 1.64 ± 0.23 h (n = 22). Cidofovir levels declined in an apparent monoexponential manner, with a mean terminal half-life of 3.98 ± 1.26 h (n = 22). The cidofovir excreted in urine in 24 h accounted for 9.40% ± 2.33% of the administered cyclic HPMPC dose. Exposure to cidofovir after intravenous administration of cyclic HPMPC was dose proportional and was 14.9% of that from an equivalent dose of cidofovir. The present study suggests that intravenous cyclic HPMPC also has a lower potential for nephrotoxicity in humans compared to that of intravenous cidofovir. The oral bioavailabilities of cyclic HPMPC were 1.76% ± 1.48% and 3.10% ± 1.16% with the administration of doses of 1.5 and 3.0 mg/kg, respectively (n = 6 per dose). The maximum concentrations of cyclic HPMPC in serum were 0.036 ± 0.021 and 0.082 ± 0.038 μg/ml after the oral administration of doses of 1.5 and 3.0 mg/kg, respectively. Cidofovir reached quantifiable levels in the serum of only one patient for each of the 1.5- and 3.0-mg/kg oral cyclic HPMPC doses.     

Pharmacokinetics and Bioavailability of the Anti-Human Immunodeficiency Virus Nucleotide Analog 9-[(R)2-(Phosphonomethoxy)Propyl]Adenine (PMPA) in Dogs

The pharmacokinetics, bioavailability, and metabolism of the anti-human immunodeficiency virus nucleotide analog 9[(R)-2-(phosphonomethoxy)propyl]adenine (PMPA) were determined in beagle dogs following intravenous, intraperitoneal, and oral administration. Fasted male beagle dogs (n = 5) were pretreated with pentagastrin and received PMPA (10 mg/kg of body weight) by the intravenous and oral routes with a washout period of 1 week between doses. A further group of male dogs received PMPA as a single dose via the intravenous (1 mg/kg; n = 5) and the intraperitoneal (10 mg/kg; n = 3) routes, with 1-week washout period between doses. The concentrations of PMPA in plasma and urine were determined over 48 h postdosing by fluorescence derivatization and high-performance liquid chromatography (HPLC). The potential for metabolism or biliary excretion of PMPA was evaluated in a dog with a chronic indwelling bile cannula. Urine, feces, and bile were collected at intervals over 48 h following the intravenous administration of [¹⁴C]PMPA (10 mg/kg; 55 μCi/kg). The concentrations of PMPA in plasma after intravenous injection were best described by an open two-compartment model with a terminal half-life of approximately 10 h. PMPA was excreted unchanged in urine (70%); recovery in feces (0.42%) or bile (0.26%) was negligible. The plasma clearance of PMPA (0.28 ± 0.05 liter/h/kg) was substantially greater than the glomerular filtration rate in this species, suggesting active tubular secretion of PMPA. No metabolites of [¹⁴C]PMPA were observed in urine, feces, or bile on the basis of HPLC with radioactive flow detection. The remainder of the dose was probably excreted unchanged in urine beyond 48 h postdosing. The mean ± standard deviation observed bioavailabilities of PMPA following oral and intraperitoneal administration at 10 mg/kg were 17.1% ± 1.88% and 73.5% ± 10.5%, respectively.     

Pharmacokinetics and Absolute Bioavailability of Oral Foscarnet in Human Immunodeficiency Virus-Seropositive Patients

The pharmacokinetics, absolute bioavailability, accumulation, and tolerability over 8 days of an oral formulation of foscarnet (90 mg/kg of body weight once daily [QD] [n = 6], 90 mg/kg twice daily [BID] [n = 6], and 180 mg/kg QD [n = 3]) were investigated in 15 asymptomatic, human immunodeficiency virus-seropositive male patients free of active cytomegalovirus infection and with normal upper gastrointestinal function. Peak plasma drug concentrations were (mean ± standard deviation) 46.4 ± 10.8 μM (90 mg/kg QD), 45.7 ± 6.9 μM (90 mg/kg BID), and 64.9 ± 31.7 μM (180 mg/kg QD) on day 1 and rose to 86.2 ± 35.8, 78.7 ± 35.2, and 86.4 ± 25.0 μM, respectively, on day 8. The mean peak concentration in plasma following the intravenous administration of foscarnet (90 mg/kg) was 887.3 ± 102.7 μM (n = 13). The terminal half-life in plasma remained unchanged, averaging 5.5 ± 2.2 h on day 1 (n = 15) and 6.6 ± 1.9 h on day 8 (n = 13), whereas it was 5.7 ± 0.7 h following intravenous dosing. Oral bioavailabilities were 9.1% ± 2.2% (90 mg/kg QD), 9.5% ± 1.7% (90 mg/kg BID), and 7.6% ± 3.7% (180 mg/kg QD); the accumulation ratios on the 8th day of dosing were 2.1 ± 1.1, 1.8 ± 0.4, and 1.7 ± 0.7, respectively. The overall 24-h urinary excretion of oral foscarnet averaged 7.8% ± 2.6% (day 1) and 13.4% ± 6.0% (day 8), whereas it was 95.0% ± 4.9% after intravenous dosing. The glomerular filtration rate and creatinine clearance remained constant, and the mean 24-h renal clearances of foscarnet for the entire study group were 96 ± 18 ml/min (day 1), 88 ± 13 ml/min (day 8), and 103 ± 16 ml/min after intravenous dosing. Adverse effects were largely confined to gastrointestinal disturbances, with all subjects experiencing diarrhea that was dose dependent in its severity. The results suggest that the formulation studied would require significant improvement with respect to tolerability and bioavailability to gain clinical acceptance.     

Is the Recommended Once-Daily Dose of Lamivudine Optimal in West African HIV-Infected Children?

We aimed in this study to describe lamivudine concentration-time courses in treatment-naïve children after once-daily administration, to study the effects of body weight and age on lamivudine pharmacokinetics, and to simulate an optimized administration scheme. For this purpose, lamivudine concentrations were measured in 49 children after at least 2 weeks of didanosine-lamivudine-efavirenz treatment. A total of 148 plasma lamivudine concentrations were measured, and a population pharmacokinetic model was developed with NONMEM. The influence of individual characteristics was tested using a likelihood ratio test. Children were divided into two groups, according to their pharmacokinetic parameters, thanks to tree regression analysis. For each patient, the area under the curve was derived from estimated individual pharmacokinetic parameters. Different once-daily doses were simulated in each group, to obtain the same exposure in children as the mean effective exposure in adults (8.9 mg/liter·h). A two-compartment model in which the slope of distribution is assumed to be equal to the absorption rate constant adequately described the data. Parameter estimates were standardized for a mean standard body weight using an allometric model. Children were then divided into 2 groups according to body weight: CL/F was significantly higher in children weighing less than 17 kg (1.12 liters/h/kg) than in children over 17 kg (0.95 liters/h/kg; P = 0.01). The target mean AUC of 8.9 mg/liters·h was obtained with a 10-mg/kg once-daily lamivudine (3TC) dose for children below 17 kg; the recommended dose of 8 mg/kg seems to be sufficient in children weighing more than 17 kg. These assumptions should be prospectively confirmed.According to the latest UNAIDS estimates, nearly 90% of the 2.5 million children infected by HIV around the world in 2007 were living in sub-Saharan Africa (21). Highly active antiretroviral therapy (HAART) has been shown to be effective in children from industrialized countries (22) and is feasible in developing countries (8, 10). The combination of didanosine (ddI), lamivudine (3TC), and efavirenz (EFV) once daily in adults showed a good antiretroviral efficacy and good long-term tolerability (9, 15). In children, the efficacy and tolerance of this ddI-3TC-EFV combination remain to be shown. The aims of the BURKINAME-ANRS 12103 trial were to estimate the pharmacokinetics of ddI, 3TC, and efavirenz given once daily in children from 30 months to 15 years or age and to evaluate the efficacy and tolerance of this drug combination.Lamivudine is rapidly absorbed following an oral dose and has a wide distribution due to its relatively low molecular mass (229 Da) and low plasma protein binding (<36%). The majority of lamivudine (approximately 70%) is eliminated unchanged in the urine over 24 h (13). Approximately 5 to 10% is metabolized to the pharmacologically inactive trans-sulfoxide metabolite, the majority of which is also excreted in the urine within 12 h after a single oral dose (13).The combination of didanosine (ddI), lamivudine (3TC), and efavirenz (EFV) once daily is associated with better compliance (9, 15). In children, maximal concentrations (C_max) and area under the concentration-time curve (AUC) from 0 to 24 h were not significantly lower with a once-daily administration of lamivudine than with a twice-daily administration (4). However, a few studies showed that younger children had a lower lamivudine exposure than older children and may be exposed to a subtherapeutic concentration, whether in a twice-daily or once-daily regimen (4, 5, 13, 17). We may wonder whether this phenomenon is due to the effect of growth (body weight) and/or maturation (age) and which parameter should be taken into account to perform dose adjustment.In the present study, lamivudine population pharmacokinetics was investigated in children in order to describe the concentration-time courses, to study the influence of covariates (body weight and age) on pharmacokinetics, and to investigate the relationships between drug concentrations and efficacy.     

Chondrotoxicity and Toxicokinetics of Sparfloxacin in Juvenile Rats

Sparfloxacin is a fluoroquinolone with improved antibacterial activity against gram-positive pathogens. Like other quinolones, use of this drug is contraindicated in children and adolescents because of its potential chondrotoxicity in juveniles. We performed histological and immunohistochemical studies on the knee joint cartilage in 5-week-old rats after treatment with 600 or 1,800 mg of sparfloxacin/kg of body weight. Treatment with single or multiple oral doses of 600 mg of sparfloxacin/kg was not sufficient to induce joint cartilage lesions. However, five of eight rats treated with a single oral dose of 1,800 mg of sparfloxacin/kg of body weight showed typical cartilage lesions in the femoral part of the knee joint. The concentrations of the drug in plasma measured 0.25, 0.75, 1.5, 3, 6, 12, and 24 h after the administration of an oral dose of 600 mg of sparfloxacin/kg were 6.3 ± 1.8, 9.2 ± 1.7, 9.6 ± 2.7, 13.0 ± 1.8, 12.3 ± 1.6, 3.4 ± 0.4, and 0.30 ± 0.20 mg/liter, respectively (mean ± standard deviation [SD]; n = 5 to 6 per group). The concentrations in plasma measured 0.75, 1.5, 3, 6, 24, and 48 h after the administration of an oral dose of 1,800 mg of sparfloxacin/kg were 10.9 ± 1.5, 15.9 ± 1.6, 19.1 ± 1.7, 14.9 ± 3.1, 4.1 ± 0.6, and 0.46 ± 0.37 mg/liter, respectively (mean ± SD; n = 3 to 4 per group). The concentrations of sparfloxacin in joint cartilage were significantly higher at all time points studied (114.8 ± 80, 99.4 ± 31.5, 84.9 ± 16.8, 44.4 ± 13.9, and 14.2 ± 4.8 mg of sparfloxacin/kg at 1.5, 3, 6, 24, and 48 h after the administration of 1,800 mg/kg, respectively). The range of concentrations in bone were similar to the range of concentrations in cartilage (peak, 115 ± 12 mg/kg after 3 h). Our data indicate that chondrotoxic doses of sparfloxacin in juvenile rats are approximately 300 times higher than the doses of sparfloxacin used therapeutically (1,800 versus approximately 6 mg/kg of body weight), but due to species differences in kinetics, concentrations in plasma differ by a factor of only approximately 15. More data on quinolone concentrations in cartilage from animals and humans could provide a better basis for a reasonable risk assessment.     

Safety, Pharmacokinetics, and Antiretroviral Activity of Intravenous 9-[2-(R)-(Phosphonomethoxy)propyl]adenine, a Novel Anti-Human Immunodeficiency Virus (HIV) Therapy, in HIV-Infected Adults

9-[2-(R)-(Phosphonomethoxy)propyl]adenine (PMPA) is a nucleotide analogue with potent antiretroviral activity in vitro and in simian models. A randomized, double-blind, placebo-controlled, dose-escalation clinical trial of intravenous PMPA monotherapy was conducted in 20 human immunodeficiency virus (HIV)-infected adults with CD4 cell counts of ≥200 cells/mm³ and plasma HIV RNA levels of ≥10,000 copies/ml. Two dose levels were evaluated (1 and 3 mg/kg of body weight/day). Ten subjects were enrolled at each dose level (eight randomized to receive PMPA and two randomized to receive placebo). On day 1, a single dose of PMPA or placebo was administered by intravenous infusion. Beginning on study day 8, PMPA or placebo was administered once daily for an additional 7 consecutive days. All subjects tolerated dosing without significant adverse events. Mean peak serum PMPA concentrations were 2.7 ± 0.9 and 9.1 ± 2.1 μg/ml in the 1- and 3-mg/kg cohorts, respectively. Serum concentrations declined in a biexponential fashion, with a terminal half-life of 4 to 8 h. At 3 mg/kg/day, a single infusion of PMPA resulted in a 0.4 log₁₀ median decline in plasma HIV RNA by study day 8. Following 7 consecutive days of study drug administration thereafter, the median changes in plasma HIV RNA from baseline were −1.1, −0.6, and 0.1 log₁₀ in the 3-mg/kg/day, 1-mg/kg/day, and placebo dose groups, respectively. Following the final dose in the 3-mg/kg/day cohort, the reduction in HIV RNA was sustained for 7 days before returning toward baseline. Further studies evaluating an oral prodrug of PMPA are under way.     

Influence of Renal Failure on Ciprofloxacin Pharmacokinetics in Rats

Ciprofloxacin pharmacokinetics have been shown to be modified in patients with renal failure (e.g., the intestinal secretion of ciprofloxacin is increased). This study investigated the influence of renal failure on the pharmacokinetics of ciprofloxacin following oral and parenteral administration to rats of a dose of 50 mg/kg of body weight. After parenteral administration, only renal clearance (CL_R) was reduced in nephrectomized rats (5.3 ± 1.4 versus 17.8 ± 4.7 ml/min/kg, P < 0.01, nephrectomized versus control rats). However, nonrenal clearance was increased in nephrectomized rats (32 ± 4 versus 15 ± 5 ml/min/kg, P < 0.01, nephrectomized versus control rats), suggesting compensatory mechanisms for reduced renal function. After oral administration, apparent total clearance and CL_R were reduced (P < 0.01) in nephrectomized rats (117 ± 25 and 6.8 ± 4.4 ml/min/kg, respectively) compared with the values for control rats (185 ± 9 and 22.6 ± 5.3 ml/min/kg, respectively) and the area under the concentration-time curve was higher (P < 0.01) for nephrectomized rats (436.3 ± 90.5 mg · min/liter) than for control rats (271.3 ± 14.3 mg · min/liter). Terminal elimination half lives in the two groups remained constant after oral and parenteral administration. These results suggest an increased bioavailability of ciprofloxacin in nephrectomized rats, which was confirmed by a nonlinear mixed-effect model.     

Disposition, metabolism, and excretion of [14C]doripenem after a single 500-milligram intravenous infusion in healthy men

In this open-label, single-center study, eight healthy men each received a single 500-mg dose of [¹⁴C]doripenem, containing 50 μCi of [¹⁴C]doripenem, administered as a 1-h intravenous infusion. The concentrations of unchanged doripenem and its primary metabolite (doripenem-M-1) resulting from β-lactam ring opening were measured in plasma and urine by a validated liquid chromatography method coupled to a tandem mass spectrometry assay. Total radioactivity was measured in blood, plasma, urine, and feces by liquid scintillation counting. Further metabolite profiling was conducted on urine samples using liquid chromatography coupled to radiochemical detection and high-resolution mass spectrometry. Unchanged doripenem and doripenem-M-1 accounted for means of 80.7% and 12.7% of the area under the plasma total-radioactivity-versus-time curve (area under the concentration-time curve extrapolated to infinity) and exhibited elimination half-lives of 1.1 and 2.5 h, respectively. Total clearance of doripenem was 16 liters/h, and renal clearance was 12.5 liters/h. At 7 days after the single dose, 95.3% of total doripenem-related radioactivity was recovered in urine and 0.72% in feces. A total mean of 97.2% of the administered dose was excreted in the urine as unchanged doripenem (78.7% ± 5.7%) and doripenem-M-1 (18.5% ± 2.6%). Most of the urinary recovery occurred within 4 h of dosing. Three additional minor metabolites were identified in urine: the glycine and taurine conjugates of doripenem-M-1 and oxidized doripenem-M-1. These results show that doripenem is predominantly eliminated in urine as unchanged drug, with only a fraction metabolized to doripenem-M-1 and other minor metabolites.     

Daptomycin Pharmacokinetics in Adult Oncology Patients with Neutropenic Fever

Daptomycin is the first antibacterial agent of the cyclic lipopeptides with in vitro bactericidal activity against gram-positive organisms, including vancomycin-resistant enterococci, methicillin-resistant staphylococci, and glycopeptide-resistant Staphylococcus aureus. The pharmacokinetics of daptomycin were determined in 29 adult oncology patients with neutropenic fever. Serial blood samples were drawn at 0, 0.5, 1, 2, 4, 8, 12, and 24 h after the initial intravenous infusion of 6 mg/kg of body weight daptomycin. Daptomycin total and free plasma concentrations were determined by high-pressure liquid chromatography. Concentration-time data were analyzed by noncompartmental methods. The results (presented as means ± standard deviations and ranges, unless indicated otherwise) were as follows: the maximum concentration of drug in plasma (C_max) was 49.04 ± 12.42 μg/ml (range, 21.54 to 75.20 μg/ml), the 24-h plasma concentration was 6.48 ± 5.31 μg/ml (range, 1.48 to 29.26 μg/ml), the area under the concentration-time curve (AUC) from time zero to infinity was 521.37 ± 523.53 μg·h/ml (range, 164.64 to 3155.11 μg·h/ml), the volume of distribution at steady state was 0.18 ± 0.05 liters/kg (range, 0.13 to 0.36 liters/kg), the clearance was 15.04 ± 6.09 ml/h/kg (range, 1.90 to 34.76 ml/h/kg), the half-life was 11.34 ± 14.15 h (range, 5.17 to 83.92 h), the mean residence time was 15.67 ± 20.66 h (range, 7.00 to 121.73 h), and the median time to C_max was 0.6 h (range, 0.5 to 2.5 h). The fraction unbound in the plasma was 0.06 ± 0.02. All patients achieved C_max/MIC and AUC from time zero to 24 h (AUC_0-24)/MIC ratios for a bacteriostatic effect against Streptococcus pneumoniae. Twenty-seven patients (93%) achieved a C_max/MIC ratio for a bacteriostatic effect against S. aureus, and 28 patients (97%) achieved an AUC_0-24/MIC ratio for a bacteriostatic effect against S. aureus. Free plasma daptomycin concentrations were above the MIC for 50 to 100% of the dosing interval in 100% of patients for S. pneumoniae and 90% of patients for S. aureus. The median time to defervescence was 3 days from the start of daptomycin therapy. In summary, a 6-mg/kg intravenous infusion of daptomycin every 24 h was effective and well tolerated in neutropenic cancer patients.     

Pharmacokinetics of the Protease Inhibitor KNI-272 in Plasma and Cerebrospinal Fluid in Nonhuman Primates after Intravenous Dosing and in Human Immunodeficiency Virus-Infected Children after Intravenous and Oral Dosing

KNI-272 is a human immunodeficiency virus (HIV) protease inhibitor with potent activity in vitro. We studied the pharmacokinetics of KNI-272 in the plasma and cerebrospinal fluid (CSF) of a nonhuman primate model and after intravenous and oral administration to children with HIV infection. Plasma and CSF were sampled over 24 h after the administration of an intravenous dose of 50 mg of KNI-272 per kg of body weight (approximately 1,000 mg/m²) to three nonhuman primates. The pharmacokinetics of KNI-272 were also studied in 18 children (9 males and 9 females; median age, 9.4 years) enrolled in a phase I trial of four dose levels of KNI-272 (100, 200, 330, and 500 mg/m² per dose given four times daily). The plasma concentration-time profile of KNI-272 in the nonhuman primate model was characterized by considerable interanimal variability and rapid elimination (clearance, 2.5 liters/h/kg; terminal half-life, 0.54 h). The level of drug exposure achieved in CSF, as measured by the area under the KNI-272 concentration-time curve, was only 1% of that achieved in plasma. The pharmacokinetics of KNI-272 in children were characterized by rapid elimination (clearance, 276 ml/min/m²; terminal half-life, 0.44 h), limited (12%) and apparently saturable bioavailability, and limited distribution (volume of distribution at steady state, 0.11 liter/kg). The concentrations in plasma were maintained above a concentration that is active in vitro for less than half of the 6-h dosing interval. There was no significant increase in CD4 cell counts or decrease in p24 antigen or HIV RNA levels. The pharmacokinetic profile of KNI-272 may limit the drug’s efficacy in vivo. It appears that KNI-272 will play a limited role in the treatment of HIV-infected children.     

Single-Dose Pharmacokinetics of a Pleconaril (VP63843) Oral Solution and Effect of Food

Pleconaril is an orally active broad-spectrum antipicornaviral agent which demonstrates excellent penetration into the central nervous system, liver, and nasal epithelium. We report the results of a randomized two-way crossover study designed to characterize the disposition of a single dose (200 mg) of pleconaril oral solution in fed and fasting humans. Twelve healthy adult subjects (18.7 to 39 years of age) participated in this study. Each subject received a single 200-mg dose of pleconaril oral solution, both coadministered with a standard English breakfast and following a 10-h predose fast. There was a minimum 7-day washout period between pleconaril doses. Repeated blood samples (n = 10) were obtained over 24 h postdose, and the pleconaril level in plasma was quantified by gas chromatography. Plasma concentration-versus-time data were curve fitted for each subject by using a nonlinear weighted least-squares algorithm, and pharmacokinetic parameters were determined from the polyexponential estimates. Pleconaril disposition was best characterized by a one-compartment open model with first-order absorption. The apparent bioavailability of pleconaril oral solution was significantly increased with the administration of food. The area under the concentration-time curve and maximum concentration of pleconaril in plasma achieved following the standard English breakfast (i.e., 9.08 ± 3.23 mg/liter · h and 1.14 ± 0.58 mg/liter, respectively) were 2.2- and 2.5-fold higher, respectively than those achieved in the fasting state (i.e., 4.08 ± 2.74 mg/liter · h and 0.46 ± 0.30 mg/liter, respectively). Mean plasma pleconaril concentrations 12 h after a single 200-mg oral dose (fed, 0.25 ± 0.2 mg/liter; fasting, 0.11 ± 0.10 mg/liter) in healthy adults remained greater than that required to inhibit more than 90% of the enteroviruses in cell culture (i.e., 0.07 mg/liter). To enhance the oral bioavailability of pleconaril, coadministration with a fat-containing meal is recommended.     

Pharmacokinetics and Safety of a New Parenteral Carbapenem Antibiotic, Biapenem (L-627), in Elderly Subjects

The pharmacokinetics and tolerability of a new parenteral carbapenem antibiotic, biapenem (L-627), were studied in healthy elderly volunteers aged 65 to 74 years (71.6 ± 2.7 years [mean ± standard deviation], n = 5; group B) and ≥75 years (77.8 ± 1.9 years, n = 5; group C), following single intravenous doses (300 and 600 mg), and compared with those of healthy young male volunteers aged 20 to 29 years (23.0 ± 3.5 years, n = 5; group A). The agent was well tolerated in all three age groups. Serial blood and urine samples were analyzed for biapenem to obtain key pharmacokinetic parameters by both two-compartment model-dependent and -independent methods. The maximum plasma concentration and area under plasma concentration-versus-time curve (AUC) increased in proportion to the dose in all three groups. Statistically significant age-related effects for AUC, total body clearance, and renal clearance (CL_R) were found, while elimination half-life (t_1/2β) and percent cumulative recovery from urine of unchanged drug (% UR) remained unaltered (t_1/2β, 1.51 ± 0.42 [300 mg] and 2.19 ± 0.64 [600 mg] h [group A], 1.82 ± 1.14 and 1.45 ± 0.36 h [group B], and 1.75 ± 0.23 and 1.59 ± 0.18 h [group C]; %UR, 52.6% ± 3.0% [300 mg] and 53.1% ± 5.1% [600 mg] [group A], 46.7% ± 7.4% and 53.0% ± 4.8% [group B], and 50.1% ± 5.2% and 47.1% ± 7.6% [group C]). A significant linear correlation was observed between the CL_R of biapenem and creatinine clearance at the dose of 300 mg but not at 600 mg. The steady-state volume of distribution tended to be decreased with age, although not significantly. Therefore, the age-related changes in parameters of biapenem described above were attributable to the combination of decreased lean body mass and lowered renal function of the elderly subjects. However, the magnitude of those changes does not necessitate dosage adjustment in elderly patients with normal renal function for their age.     

Repeated-Dose Pharmacokinetics of an Oral Solution of Itraconazole in Infants and Children

The safety, tolerability, and pharmacokinetics of an oral solution of itraconazole and its active metabolite hydroxyitraconazole were investigated in an open multicenter study of 26 infants and children aged 6 months to 12 years with documented mucosal fungal infections or at risk for the development of invasive fungal disease. The most frequent underlying illness was acute lymphoblastic leukemia, except in the patients aged 6 months to 2 years, of whom six were liver transplant recipients. The patients were treated with itraconazole at a dosage of 5 mg/kg of body weight once daily for 2 weeks. Blood samples were taken after the first dose, during treatment, and up to 8 days after the last itraconazole dose. On day 1, the mean peak concentrations in plasma after the first and last doses (C_max) and areas under the concentration-time curve from 0 to 24 h (AUC_0–24) for itraconazole and hydroxyitraconazole were lower in the children aged 6 months to 2 years than in children aged 2 to 12 years but were comparable on day 14. The mean AUC_0–24-based accumulation factors of itraconazole and hydroxyitraconazole from day 1 to 14 ranged from 3.3 to 8.6 and 2.3 to 11.4, respectively. After 14 days of treatment, C_max, AUC_0–24, and the half-life, respectively, were (mean ± standard deviation) 571 ± 416 ng/ml, 6,930 ± 5,830 ng · h/ml, and 47 ± 55 h in the children aged 6 months to 2 years; 534 ± 431 ng/ml, 7,330 ± 5,420 ng · h/ml, and 30.6 ± 25.3 h in the children aged 2 to 5 years; and 631 ± 358 ng/ml, 8,770 ± 5,050 ng · h/ml, and 28.3 ± 9.6 h in the children aged 5 to 12 years. There was a tendency to have more frequent low minimum concentrations of the drugs in plasma for both itraconazole and hydroxyitraconazole for the children aged 6 months to 2 years. The oral bioavailability of the solubilizer hydroxypropyl-β-cyclodextrin was less than 1% in the majority of the patients. In conclusion, an itraconazole oral solution given at 5 mg/kg/day provides potentially therapeutic concentrations in plasma, which are, however, substantially lower than those attained in adult cancer patients, and is well tolerated and safe in infants and children.     

Posaconazole Pharmacodynamic Target Determination against Wild-Type and Cyp51 Mutant Isolates of Aspergillus fumigatus in an In Vivo Model of Invasive Pulmonary Aspergillosis

Invasive pulmonary aspergillosis (IPA) is a devastating disease of immunocompromised patients. Pharmacodynamic (PD) examination of antifungal drug therapy in IPA is one strategy that may improve outcomes. The current study explored the PD target of posaconazole in an immunocompromised murine model of IPA against 10 A. fumigatus isolates, including 4 Cyp51 wild-type isolates and 6 isolates carrying Cyp51 mutations conferring azole resistance. The posaconazole MIC range was 0.25 to 8 mg/liter. Following infection, mice were given 0.156 to 160 mg/kg of body weight of oral posaconazole daily for 7 days. Efficacy was assessed by quantitative PCR (qPCR) of lung homogenate and survival. At the start of therapy, mice had 5.59 ± 0.19 log₁₀ Aspergillus conidial equivalents (CE)/ml of lung homogenate, which increased to 7.11 ± 0.29 log₁₀ CE/ml of lung homogenate in untreated animals. The infection was uniformly lethal prior to the study endpoint in control mice. A Hill-type dose response function was used to model the relationship between posaconazole free drug area under the concentration-time curve (AUC)/MIC and qPCR lung burden. The static dose range was 1.09 to 51.9 mg/kg/24 h. The free drug AUC/MIC PD target was 1.09 ± 0.63 for the group of strains. The 1-log kill free drug AUC/MIC was 2.07 ± 1.02. The PD target was not significantly different for the wild-type and mutant organism groups. Mortality mirrored qPCR results, with the greatest improvement in survival noted at the same dosing regimens that produced static or cidal activity. Consideration of human pharmacokinetic data and the current static dose PD target would predict a clinical MIC threshold of 0.25 to 0.5 mg/liter.     

Prospective,Controlled Study of Acyclovir Pharmacokinetics in Obese Patients

The current recommendations for intravenous (i.v.) acyclovir dosing in obese patients suggest using ideal body weight (IBW) rather than total body weight (TBW). To our knowledge, no pharmacokinetic analysis has validated this recommendation. This single-dose pharmacokinetic study was conducted in an inpatient oncology population. Enrollment was conducted by 1:1 matching of obese patients (>190% of IBW) to normal-weight patients (80 to 120% of IBW). All patients received a single dose of i.v. acyclovir, 5 mg/kg, infused over 60 min. Consistent with current recommendations, IBW was used for obese patients and TBW for normal-weight patients. Serial plasma concentrations were obtained and compared. Seven obese and seven normal-weight patients were enrolled, with mean body mass indexes of 45.0 and 22.5 kg/m², respectively. Systemic clearance was substantially higher in the obese than normal-weight patients (mean, 19.4 ± 5.3 versus 14.3 ± 5.4 liters/h; P = 0.047). Area under the concentration-time curve was lower in the obese patients (15.2 ± 2.9 versus 24.0 ± 9.4 mg · h/liter; P = 0.011), as was maximum concentration (5.8 ± 0.9 versus 8.2 ± 1.3 mg/liter; P = 0.031). Utilization of IBW for dose calculation of i.v. acyclovir in obese patients leads to lower systemic exposure than dosing by TBW in normal-weight patients. While not directly evaluated in this study, utilization of an adjusted body weight for dose determination appears to more closely approximate the exposure seen in normal-weight patients. (This study has been registered at ClinicalTrials.gov under registration no. NCT01714180.)     

Optimizing the Initial Amikacin Dosage in Adults

We report on the pharmacokinetics (PK) and pharmacodynamics (PD) of high-dose (>15 mg/kg of body weight per day) amikacin. A mean (standard deviation [SD]) maximum drug concentration in the serum (C_max) and 24-h area under the concentration-time curve (AUC₂₄) of 101 (49.4) mg/liter and 600 (387) mg · h/liter, respectively, were observed (n = 73) with 28.0 (8.47) mg/kg/day doses. An initial amikacin dose of 2,500 mg in adults weighing 40 kg to 200 kg with therapeutic drug monitoring to adjust the maintenance dose will optimize its PK and PD.     

Determination of Appropriate Weight-Based Cutoffs for Empiric Cefazolin Dosing Using Data from a Phase 1 Pharmacokinetics and Safety Study of Cefazolin Administered for Surgical Prophylaxis in Pediatric Patients Aged 10 to 12 Years

Despite over 40 years of worldwide usage, relatively few data have been published on the pharmacokinetics of cefazolin in pediatric surgical patients. The primary objectives of this study were to examine the pharmacokinetics and safety of cefazolin in children 10 to 12 years of age (inclusive) receiving 1 or 2 g of cefazolin, based on body weight. This multiple-center, open-label study enrolled pediatric patients electively scheduled for surgical procedures who required cefazolin as part of their routine clinical management. Patients weighing ≥25 to <50 kg received a 1-g dose, and patients weighing ≥50 to ≤85 kg received a 2-g dose. Postdose pharmacokinetic and safety assessments were conducted following drug administration. Cefazolin concentration-time data were analyzed by using both noncompartmental and population pharmacokinetics methods. Monte Carlo simulations were performed to identify appropriate weight-based cutoffs for the dosing of children aged 10 to 17 years of age. Twelve patients were enrolled in this study and provided the requisite pharmacokinetic data. In general, cefazolin was well tolerated. The mean cefazolin terminal elimination half-life, clearance, and area under the concentration-time curve from time zero to infinity in this population were 1.95 h, 0.804 ml/min/kg, and 607 mg · h/liter, respectively. Patients weighing 50 to 60 kg exhibited elevated cefazolin exposures. Observed pharmacokinetic parameters and simulation results indicated that a weight-based cutoff of 60 kg is predicted to provide cefazolin exposure consistent with that observed in normal, healthy adults at recommended doses for surgical prophylaxis. (This study has been registered at ClinicalTrials.gov under registration no. {"type":"clinical-trial","attrs":{"text":"NCT01904357","term_id":"NCT01904357"}}NCT01904357.)     

Pharmacodynamics of Gatifloxacin in Cerebrospinal Fluid in Experimental Cephalosporin-Resistant Pneumococcal Meningitis

The purpose of this study was to evaluate the cerebrospinal fluid (CSF) pharmacodynamics of a new fluoroquinolone, gatifloxacin (AM-1155), in experimental pneumococcal meningitis. The penetration of gatifloxacin into CSF, calculated as the percentage of the area under the concentration-time curve (AUC) in CSF over the AUC in blood, was 46 to 56%. Gatifloxacin showed linear pharmacokinetics in CSF, and 1 h after intravenous dosages of 7.5, 15, or 30 mg/kg of body weight, peak CSF concentrations were 0.46 ± 0.08 (mean ± standard deviation), 0.94 ± 0.16, and 1.84 ± 0.5 μg/ml, respectively. The elimination half-life of gatifloxacin in CSF was 3.8 to 5.6 h (compared with 2.7 to 3.2 h in blood). There was a significant interrelationship among the highest measured values of gatifloxacin in blood and CSF/minimal bactericidal concentration (C_peak/MBC), the time antibiotic concentrations exceeded the MBC (T > MBC), and AUC/MBC (r = 0.94); in single-dose experiments, each correlated significantly with the bacterial killing rate. Divided-dose regimens, resulting in greater T > MBC values but lower C_peak/MBC ratios, were more effective in terms of bacterial clearance compared with corresponding single-dose regimens. Gatifloxacin therapy was as effective as currently recommended regimens (e.g., a combination of ceftriaxone and vancomycin) against this highly cephalosporin-resistant pneumococcal strain. The bactericidal activity of gatifloxacin in CSF was closely related to the AUC/MBC ratio, but maximal activity was achieved only when drug concentrations exceeded the MBC for the entire dosing interval.     

In Vivo Activity and Pharmacokinetic Evaluation of a Novel Long-Acting Carbapenem Antibiotic, MK-826 (L-749,345)

MK-826 (formerly L-749,345), is a potent 1-β-methyl carbapenem with a long half-life and broad spectrum of activity. This compound is presently in phase-II clinical trials. Its activity against a number of gram-positive and gram-negative organisms was compared to those of imipenem (IPM) and eight other β-lactam agents in two in vivo murine infection models. The distribution in tissue and pharmacokinetic properties of MK-826 and ceftriaxone (CTRX) were also evaluated in CD-1 mice following a single intraperitoneal dose (10 mg/kg of body weight). In addition, concentrations in plasma as well as biliary and urinary recovery of MK-826 were compared to that of CTRX in a cannulated rat model. In a localized murine thigh infection model, MK-826 and IPM were superior to a variety of β-lactam antibiotics in reduction of Staphylococcus aureus CFU compared with results from nontreated controls (eliminating ≥4 log₁₀ CFU). Similar activities of IPM and MK-826 were observed in a gram-positive bacterial murine systemic infection model. While IPM demonstrated greater efficacy than MK-826 against Enterobacter cloacae (50% effective doses [ED₅₀s] of 0.062 and 0.227 mg/kg, respectively) and Pseudomonas aeruginosa (ED₅₀s of 0.142 and 3.0 mg/kg, respectively) systemic infections, MK-826 was 8- to 350-fold more efficacious than IPM against all other gram-negative organisms in this infection model. In mice, MK-826 demonstrated a higher peak concentration in serum (62.8 versus 42.6 μg/ml) and a larger area under the curve (AUC) (150.8 versus 90.0 μg · hr/ml) than CTRX. The concentrations of MK-826 and CTRX in serum declined slowly, with levels of 3.6 and 2.0 μg/ml remaining, respectively, at 6 h posttreatment. The rat pharmacokinetic model showed the average AUC of MK-826 to be greater than that of CTRX (284 versus 142 μg · hr/ml) following a single 10-mg/kg dose. Also, a half-life of MK-826 longer than that of CTRX (3.2 versus 2.3 h) was observed in this species. The total amount of drug excreted in the bile in 8 h was greater for CTRX (55 to 64% of the dose) than for MK-826 (6 to 12.5% of the dose). Urinary recovery was similar for both antibiotics, with 16 to 18% of the dose recovered over an 8-h period. This excellent broad-spectrum in vivo efficacy of MK-826, together with advantageous pharmacokinetics, supports the argument for its further clinical development.     

Zalcitabine Population Pharmacokinetics: Application of Radioimmunoassay

Zalcitabine population pharmacokinetics were evaluated in 44 human immunodeficiency virus-infected patients (39 males and 5 females) in our immunodeficiency clinic. Eighty-one blood samples were collected during routine clinic visits for the measurement of plasma zalcitabine concentrations by radioimmunoassay (1.84 ± 1.24 samples/patient; range, 1 to 6 samples/patient). These data, along with dosing information, age (38.6 ± 7.13 years), sex, weight (79.1 ± 15.0 kg), and estimated creatinine clearance (89.1 ± 21.5 ml/min), were entered into NONMEM to obtain population estimates for zalcitabine pharmacokinetic parameters (4). The standard curve of the radioimmunoassay ranged from 0.5 to 50.0 ng/ml. The observed concentrations of zalcitabine in plasma ranged from 2.01 to 8.57 ng/ml following the administration of doses of either 0.375 or 0.75 mg. A one-compartment model best fit the data. The addition of patient covariates did not improve the basic fit of the model to the data. Oral clearance was determined to be 14.8 liters/h (0.19 liter/h/kg; coefficient of variation [CV] = 23.8%), while the volume of distribution was estimated to be 87.6 liters (1.18 liters/kg; CV = 54.0%). We were also able to obtain individual estimates of oral clearance (range, 8.05 to 19.8 liters/h; 0.11 to 0.30 liter/h/kg) and volume of distribution (range, 49.2 to 161 liters; 0.43 to 1.92 liters/kg) of zalcitabine in these patients with the POSTHOC option in NONMEM. Our value for oral clearance agrees well with other estimates of oral clearance from traditional pharmacokinetic studies of zalcitabine and suggests that population methods may be a reasonable alternative to these traditional approaches for obtaining information on the disposition of zalcitabine.