Serum and Cerebrospinal Fluid Pharmacokinetics of Intravenous and Oral Lamivudine in Human Immunodeficiency Virus-Infected Children

We studied the pharmacokinetics of intravenously and orally administered lamivudine at six dose levels ranging from 0.5 to 10 mg/kg of body weight in 52 children with human immunodeficiency virus infection. A two-compartment model with first-order elimination from the central compartment was simultaneously fitted to the serum drug concentration-time data obtained after intravenous and oral administration. The maximal concentration at the end of the 1-h intravenous infusion and the area under the concentration-time curve after oral and intravenous administration increased proportionally with the dose. The mean clearance of lamivudine (± standard deviation) in the children was 0.53 ± 0.19 liter/kg/h (229 ± 77 ml/min/m² of body surface area), and the mean half-lives at the distribution and elimination phases were 0.23 ± 0.18 and 2.2 ± 2.1 h, respectively. Clearance was age dependent when normalized to body weight but age independent when normalized to body surface area. Lamivudine was rapidly absorbed after oral administration, and 66% ± 25% of the oral dose was absorbed. Serum lamivudine concentrations were maintained above 1 μM for ≥8 h of 24 h on the twice daily oral dosing schedule with doses of ≥2 mg/kg. The cerebrospinal fluid drug concentration measured 2 to 4 h after the dose was 12% (range, 0 to 46%) of the simultaneously measured serum drug concentration. A limited-sampling strategy was developed to estimate the area under the concentration-time curve for concentrations in serum at 2 and 6 h.     

A phase I/II study of the safety and activity of a microsphere formulation of KNI-272 in patients with HIV-1 infection

Eighteen patients with symptomatic HIV disease were enrolled into a phase I/II study of a microsphere formulation of the HIV protease inhibitor KNI-272, with doses escalated up to a maximum dose of 60 mg/kg/day. One patient developed reversible elevation in hepatic transaminase. The plasma half-life of the drug was very short, varying between 0.25 and 1.1 h. No consistent effect on plasma HIV RNA levels or CD4(+) lymphocyte counts was seen.     

Cerebrospinal fluid and plasma pharmacokinetics of morphine infusions in pediatrie cancer patients and rhesus monkeys

The cerebrospinal fluid (CSF) and plasma pharmacokinetics of morphine administered as a continuous infusion were studied in pediatric cancer patients and in monkeys with implanted Ommaya reservoirs.

In monkeys administered a constant infusion of 0.15 mg morphine sulfate/kg/h, morphine steady-state plasma and CSF concentrations were 84.4 ±20.0 ng/ml and 25.3 ± 4.9 ng/ml, respectively, for a CSF : plasma ratio of 0.30 ± 0.05. For comparison, the monkeys also received morphine as an intravenous bolus at a dose of 0.45 mg morphine sulfate/kg. The CSF:plasma area under the concentration-time curve (AUC) ratio was 0.40 ± 0.07, similar to that seen with continuous infusion.

Morphine pharmacokinetics were also studied in cancer patients administered long-term infusions of morphine sulfate over a wide dosage range (0.04–31 mg/kg/h). The steady-state plasma concentration of morphine was linearly related to the infusion rate although variability was noted. The average clearance value was 23 ml/min/kg which is at the upper end of the estimates reported for morphine clearance using bolus administration. No evidence for morphine accumulation using long-term administration was observed. A limited number of CSF samples obtained by lumbar puncture showed comparable CSF and plasma concentrations of unbound morphine assuming morphine is approximately 30% bound in human plasma.     

In vitro anti-human immunodeficiency virus (HIV) activities of transition state mimetic HIV protease inhibitors containing allophenylnorstatine.

Transition state mimetic tripeptide human immunodeficiency virus (HIV) protease inhibitors containing allophenylnorstatine [(2S,3S)-3-amino-2-hydroxy-4-phenylbutyric acid] were synthesized and tested for activity against HIV in vitro. Two compounds, KNI-227 and KNI-272, which were highly potent against HIV protease with little inhibition of other aspartic proteases, showed the most potent activity against the infectivity and cytopathic effect of a wide spectrum of HIV strains. As tested in target CD4+ ATH8 cells, the 50% inhibitory concentrations of KNI-227 against HIV type 1 LAI (HIV-1LAI), HIV-1RF, HIV-1MN, and HIV-2ROD were 0.1, 0.02, 0.03, and 0.1 microM, respectively, while those of KNI-272 were 0.1, 0.02, 0.04, and 0.1 microM, respectively. Both agents completely blocked the replication of 3'-azido-2',3'-dideoxythymidine-sensitive and -insensitive clinical HIV-1 isolates at 0.08 microM as tested in target phytohemagglutinin-activated peripheral blood mononuclear cells. The ratios of 50% cytotoxic concentrations to 50% inhibitory concentrations for KNI-227 and KNI-272 were approximately 2,500 and > 4,000, respectively, as assessed in peripheral blood mononuclear cells. Both compounds blocked the posttranslational cleavage of the p55 precursor protein to generate the mature p24 Gag protein in stably HIV-1-infected cells. The n-octanol-water partition coefficients of KNI-227 and KNI-272 were high, with log Po/w values of 3.79 and 3.56, respectively. Degradation of KNI-227 and KNI-272 in the presence of pepsin (1 mg/ml, pH 2.2) at 37 degrees C for 24 h was negligible. Current data warrant further careful investigations toward possible clinical application of these two novel compounds.     

Low penetration of oseltamivir and its carboxylate into cerebrospinal fluid in healthy Japanese and Caucasian volunteers

Oseltamivir is a potent, well-tolerated antiviral for the treatment and prophylaxis of influenza. Although no relationship with treatment could be demonstrated, recent reports of abnormal behavior in young individuals with influenza who were receiving oseltamivir have generated renewed interest in the central nervous system (CNS) tolerability of oseltamivir. This single-center, open-label study explored the pharmacokinetics of oseltamivir and oseltamivir carboxylate (OC) in the plasma and cerebrospinal fluid (CSF) of healthy adult volunteers over a 24-hour interval to determine the CNS penetration of both these compounds. Four Japanese and four Caucasian males were enrolled in the study. Oseltamivir and OC concentrations in CSF were low (mean of observed maximum concentrations [C_max], 2.4 ng/ml [oseltamivir] and 19.0 ng/ml [OC]) versus those in plasma (mean C_max, 115 ng/ml [oseltamivir] and 544 ng/ml [OC]), with corresponding C_max CSF/plasma ratios of 2.1% (oseltamivir) and 3.5% (OC). Overall exposure to oseltamivir and OC in CSF was also comparatively low versus that in plasma (mean area under the concentration-time curve CSF/plasma ratio, 2.4% [oseltamivir] and 2.9% [OC]). No gross differences in the pharmacokinetics of oseltamivir or OC were observed between the Japanese and Caucasian subjects. Oseltamivir was well tolerated. This demonstrates that the CNS penetration of oseltamivir and OC is low in Japanese and Caucasian adults. Emerging data support the idea that oseltamivir and OC have limited potential to induce or exacerbate CNS adverse events in individuals with influenza. A disease- rather than drug-related effect appears likely.     

Population Pharmacokinetics of Acyclovir in Children and Young People with Malignancy after Administration of Intravenous Acyclovir or Oral Valacyclovir

Acyclovir is effective in the prevention and treatment of herpes simplex virus (HSV) and varicella-zoster virus (VZV) infections. The aim of this study was to characterize the population pharmacokinetics of acyclovir observed following treatment with intravenous acyclovir and oral valacyclovir (valaciclovir) in young people with malignancy. Plasma acyclovir concentration-time data were collected from 43 patients (age range, 9 months to 20 years) who had been given multiple doses of acyclovir (5 mg/kg of body weight) and/or valacyclovir (10 mg/kg). Nonlinear mixed-effect modeling was employed to analyze acyclovir population pharmacokinetics and identify influential covariates. Simulations (n = 1,000) were conducted to explore the ability of the current doses to maintain acyclovir concentrations above the recommended 50% inhibitory concentration for HSV or VZV (0.56 mg/liter or 1.125 mg/liter, respectively) for more than 12 h. A one-compartment pharmacokinetic model with first-order elimination best described the acyclovir concentration-time data. The population mean estimates for clearance (CL), volume of distribution (V), absorption rate (k_a), and bioavailability (F) were 3.55 liters/h, 7.36 liters, 0.63 h⁻¹, and 0.60, respectively. Inclusion of body weight and estimated creatinine CL (CL_CR) in the final model reduced the interindividual variabilities in CL and V from 61% to 24% and from 75% to 36%, respectively. Simulations revealed that with the use of the current doses, maximal efficacy can be achieved in over 45% of patients weighing 25 to 50 kg and with CL_CR levels of 2.0 to 4.0 liters/h/m², but only in a much smaller proportion of patients, with low weights (10 kg) and high CL_CRs (5.5 liters/h/m²), suggesting that higher doses are required for this subgroup. This validated population pharmacokinetic model for acyclovir may be used to develop dosing guidelines for safe and effective antiviral therapy in young people with malignancy.Acyclovir {9-[(2-hydroxyethoxy)-methyl]guanine} is an antiviral agent which has been shown to be effective in the prevention and treatment of herpes simplex virus (HSV) (33) and varicella-zoster virus (VZV) infections (3). It is also used for prophylaxis of cytomegalovirus infection following solid organ transplantation (1). Acyclovir exhibits a selective inhibition of herpes virus replication and has potent clinical antiviral activity against HSV and VZV, which can cause significant morbidity and mortality due to primary infection or to reactivation following long-term latency in pediatric oncology and pediatric bone marrow/stem cell transplantation (16, 24). Children with malignant diseases who experience prolonged periods of myelosuppression due to cytotoxic chemotherapy or hematopoietic stem cell transplant are highly susceptible to invasive viral infections (16). The use of indwelling vascular catheters further increases the risk of development of invasive viral infections among immunosuppressed children (20).The efficacy of oral acyclovir may be limited by its low oral bioavailability (F), which is between 15% and 30% (17). Valacyclovir (valaciclovir), the l-valyl ester prodrug of acyclovir, is rapidly and extensively converted to acyclovir after oral administration (42) and can increase the oral F value of acyclovir up to 50% (37).Following administration of acyclovir or valacyclovir, approximately 10% of its dose is metabolized in the liver (17). Acyclovir is predominately eliminated by renal excretion via glomerular filtration and tubular secretion (17, 23). A patient''s renal function significantly influences the pharmacokinetics of acyclovir, with the mean systemic clearances (CLs) of acyclovir being 327 ± 80, 248 ± 62, and 190 ± 62 ml/min/1.73 m² in adult patients, with estimated creatinine CLs (CL_CRs) of >80, 50 to 80, and 15 to 50 ml/min/1.73 m², respectively (8).Moreover, renal impairment is a commonly reported adverse effect of acyclovir (approved product information for acyclovir; Mayne Pharma Pty., Ltd., Victoria, Australia [http://mims.hcn.net.au]). For intravenous dosing, acyclovir must be infused over 1 hour to avoid high concentrations, as acyclovir sodium can precipitate as crystals in the renal tubules, with the risk of tubular damage (approved product information for acyclovir; Mayne Pharma Pty., Ltd.). Hence, the dosage of acyclovir or valacyclovir may need to be reduced, and the dosing interval may need to be increased, in patients with renal impairment to reduce the risk of acyclovir-induced neurotoxicity due to drug accumulation (15, 18).Acyclovir demonstrates high interindividual variability (IIV) in its treatment response (2, 27, 29), with a wide range of adverse reactions. While the current dosage recommendations for acyclovir and valacyclovir are based on body weight (5 mg/kg and 10 mg/kg of body weight, respectively), there are no specific recommendations for reduction of the acyclovir dose in pediatric patients with renal impairment, with the exception of some data for neonates (10). Valacyclovir is used in the clinical setting because of its significantly high F value compared with that of oral acyclovir (37). However, information regarding its optimal use in children is limited because pharmacokinetic data are lacking and the safety and effectiveness of valacyclovir in children have not been established (approved product information for valacyclovir; GlaxoSmithKline Pty., Ltd., Victoria, Australia [http://mims.hcn.net.au]).The aims of this study were to characterize the pharmacokinetics of acyclovir following intravenous infusion of acyclovir and oral administration of valacyclovir, to investigate patient factors which contribute to the wide IIV in acyclovir pharmacokinetics, and to evaluate the current dose regimens by using a simulation approach for children and young people with malignancy.     

Zidovudine concentration in brain extracellular fluid measured by microdialysis: steady-state and transient results in rhesus monkey

We measured zidovudine concentrations in blood, muscle, and brain extracellular fluid (ECF) by microdialysis and in serum ultrafiltrate and cerebrospinal fluid (CSF) samples during a continuous intravenous infusion (15 mg/kg/h) and after bolus dosing (50-80 mg/kg over 15 min) in nonhuman primates to determine whether CSF drug penetration is a valid surrogate for blood-brain barrier penetration. Recovery was estimated in vivo by zero net flux for the continuous infusion and retrodialysis for the bolus dosing. In vivo recovery was tissue-dependent and was lower in brain than in blood or muscle. Mean (+/-S.D.) steady-state blood, muscle, and brain zidovudine concentrations by microdialysis were 112 +/- 63.8, 105 +/- 51.1, and 13.8 +/- 10.4 microM, respectively; and steady-state serum ultrafiltrate and CSF concentrations were 81.2 +/- 40.2 and 14.1 +/- 8.0 microM, respectively. Brain ECF penetration (microdialysis brain/blood ratio) and CSF penetration (standard sampling CSF/serum ratio) at steady state were 0.13 +/- 0.06 and 0.17 +/- 0.02, respectively. With bolus dosing the mean (+/-S.D.) zidovudine area under concentration-time curve (AUC) normalized to a dose of 80 mg/kg was 577 +/- 103 microM. h in blood, 528 +/- 202 microM. h in muscle, and 108 +/- 74 microM. h in brain (brain/blood ratio of 0.18 +/- 0.10) by microdialysis. Serum ultrafiltrate AUC was 446 +/- 72 microM. h and the CSF AUC was 123 +/- 4.7 microM. h (CSF/serum ratio of 0.28 +/- 0.06). In conclusion, recovery was tissue-dependent. CSF and brain ECF zidovudine concentrations were comparable at steady state, and the corresponding AUCs were comparable after bolus injection. Thus, zidovudine penetration in brain ECF and CSF in nonhuman primates is limited to a similar extent, presumably by active transport, as in other species.     

Efficacy of oritavancin in a murine model of Bacillus anthracis spore inhalation anthrax

The inhaled form of Bacillus anthracis infection may be fatal to humans. The current standard of care for inhalational anthrax postexposure prophylaxis is ciprofloxacin therapy twice daily for 60 days. The potent in vitro activity of oritavancin, a semisynthetic lipoglycopeptide, against B. anthracis (MIC against Ames strain, 0.015 μg/ml) prompted us to test its efficacy in a mouse aerosol-anthrax model. In postexposure prophylaxis dose-ranging studies, a single intravenous (i.v.) dose of oritavancin of 5, 15, or 50 mg/kg 24 h after a challenge with 50 to 75 times the median lethal dose of Ames strain spores provided 40, 70, and 100% proportional survival, respectively, at 30 days postchallenge. Untreated animals died within 4 days of challenge, whereas 90% of control animals receiving ciprofloxacin at 30 mg/kg intraperitoneally twice daily for 14 days starting 24 h after challenge survived. Oritavancin demonstrated significant activity post symptom development; a single i.v. dose of 50 mg/kg administered 42 h after challenge provided 56% proportional survival at 30 days. In a preexposure prophylaxis study, a single i.v. oritavancin dose of 50 mg/kg administered 1, 7, 14, or 28 days before lethal challenge protected 90, 100, 100, and 20% of mice at 30 days; mice treated with ciprofloxacin 24 h or 24 and 12 h before challenge all died within 5 days. Efficacy in pre- and postexposure models of inhalation anthrax, together with a demonstrated low propensity to engender resistance, promotes further study of oritavancin pharmacokinetics and efficacy in nonhuman primate models.     

Pharmacokinetics,Microbial Response,and Pulmonary Outcomes of Multidose Intravenous Azithromycin in Preterm Infants at Risk for Ureaplasma Respiratory Colonization

The study objectives were to refine the population pharmacokinetics (PK) model, determine microbial clearance, and assess short-term pulmonary outcomes of multiple-dose azithromycin treatment in preterm infants at risk for Ureaplasma respiratory colonization. Fifteen subjects (7 of whom were Ureaplasma positive) received intravenous azithromycin at 20 mg/kg of body weight every 24 h for 3 doses. Azithromycin concentrations were determined in plasma samples obtained up to 168 h post-first dose by using a validated liquid chromatography-tandem mass spectrometry method. Respiratory samples were obtained predose and at three time points post-last dose for Ureaplasma culture, PCR, antibiotic susceptibility testing, and cytokine concentration determinations. Pharmacokinetic data from these 15 subjects as well as 25 additional subjects (who received either a single 10-mg/kg dose [n = 12] or a single 20-mg/kg dose [n = 13]) were analyzed by using a nonlinear mixed-effect population modeling (NONMEM) approach. Pulmonary outcomes were assessed at 36 weeks post-menstrual age and 6 months adjusted age. A 2-compartment model with all PK parameters allometrically scaled on body weight best described the azithromycin pharmacokinetics in preterm neonates. The population pharmacokinetics parameter estimates for clearance, central volume of distribution, intercompartmental clearance, and peripheral volume of distribution were 0.15 liters/h · kg^0.75, 1.88 liters · kg, 1.79 liters/h · kg^0.75, and 13 liters · kg, respectively. The estimated area under the concentration-time curve over 24 h (AUC₂₄)/MIC₉₀ value was ∼4 h. All posttreatment cultures were negative, and there were no drug-related adverse events. One Ureaplasma-positive infant died at 4 months of age, but no survivors were hospitalized for respiratory etiologies during the first 6 months (adjusted age). Thus, a 3-day course of 20 mg/kg/day intravenous azithromycin shows preliminary efficacy in eradicating Ureaplasma spp. from the preterm respiratory tract.     

Pharmacokinetics of dideoxypurine nucleoside analogs in plasma and cerebrospinal fluid of rhesus monkeys.

The pharmacokinetics of 2',3'-dideoxyadenosine (ddA), didanosine, 2',3'-dideoxyguanosine (ddG), and 6-halogenated prodrugs of ddG, 6-chloro-ddG and 6-iodo-ddG, in plasma and cerebrospinal fluid (CSF) were studied in a non-human primate model. ddA was rapidly and completely deaminated to didanosine, such that didanosine concentration profiles in plasma and CSF were identical following administration of ddA and didanosine. The mean clearance of didanosine was 0.50 liters/h/kg, the terminal half-life was 1.8 h, and the CSF-to-plasma ratio was 4.8%. The disposition of ddG was similar, with a clearance of 0.70 liters/h/kg and a half-life of 1.7 h. The adenosine deaminase-mediated conversion of the 6-halogenated-ddG prodrugs to ddG was rapid but incomplete (48% for 6-chloro-ddG and 29% for 6-iodo-ddG). The CSF-to-plasma ratios of ddG with equimolar doses of ddG, 6-chloro-ddG, and 6-iodo-ddG were 8.5, 24, and 17%, respectively, but the actual ddG exposures in CSF (area under the CSF concentration-time curve) were comparable for ddG (12.1 microM.h) and the 6-halogenated-ddG prodrugs (18.8 microM.h for 6-chloro-ddG, 9.3 microM.h for 6-iodo-ddG).6-Chloro-ddG was not detectable in plasma or CSF, and the CSF-to-plasma ratio of 6-iodo-ddG was 9.4%, so the higher CSF-to-plasma ratios of ddG with the administration of the 6-halogenated-ddG prodrugs does not appear to be the result of enhanced penetration of the prodrug and subsequent dehalogenation to ddG. The penetration of ddG into CSF exceeds that of didanosine and is enhanced by administration of the 6-halogenated prodrugs, although the mechanism of this enhanced penetration is unclear.     

Protein binding of human immunodeficiency virus protease inhibitor KNI-272 and alteration of its in vitro antiretroviral activity in the presence of high concentrations of proteins.

KNI-272 represents a peptide-based protease inhibitor having potent antiretroviral activity against human immunodeficiency virus (HIV) in vitro. The structure contains allophenylnorstatine [(2S,3S)-3-amino-2-hydroxy-4-phenylbutyric acid] with a hydroxymethylcarbonyl isostere. We asked whether this experimental anti-HIV agent could exert its activity in vitro in the presence of relatively high concentrations of fetal calf serum (FCS) and assessed its protein-binding properties by using fresh human plasma preparations. The 50 and 75% inhibitory concentrations of KNI-272 against HIV type 1 replication in vitro were 3- to 5-fold and 5-fold higher in the presence of 50% FCS and 15- to 25-fold and 25- to 100-fold higher in the presence of 80% ECS, respectively, than those with 15% FCS, whereas the antiviral activity of 2',3'-dideoxyinosine was not significantly affected by FCS concentrations in the culture. Detailed studies of the protein binding of KNI-272 suggest that in human plasma binding occurs predominantly to alpha 1-acid glycoprotein and that KNI-272 is probably extensively (approximately 98 to 99%) protein bound at concentrations likely to be achieved in the circulation. Thus, higher levels of KNI-272 in plasma may be required when this compound undergoes clinical trials relative to those inferred from in vitro data involving the use of 10 to 15% FCS-containing culture media. The current data may have a relevance to other antiretroviral drugs that are under development and that have a high protein-binding capacity.     

Mass Balance and Pharmacokinetics of [14C]Telavancin following Intravenous Administration to Healthy Male Volunteers

The mass balance and pharmacokinetics of telavancin, a semisynthetic lipoglycopeptide antimicrobial agent, were characterized in an open-label, phase 1 study of six healthy male subjects. After a single 1-h intravenous infusion of 10 mg/kg [¹⁴C]telavancin (0.68 μCi/kg), blood, urine, and feces were collected at regular intervals up to 216 h postdose. Whole blood, plasma, urine, and fecal samples were assayed for total radioactivity using scintillation counting; plasma and urine were also assayed for parent drug and metabolites using liquid chromatography with tandem mass spectrometry. The concentration-time profiles for telavancin and total radioactivity in plasma were comparable from 0 to 24 h after the study drug administration. Telavancin accounted for >95% and 83% of total radioactivity in plasma at 12 h and 24 h, respectively. By 216 h, approximately 76% of the total administered dose was recovered in urine while only 1% was collected in feces. Unchanged telavancin accounted for most (83%) of the eliminated dose. Telavancin metabolite THRX-651540 along with two other hydroxylated metabolites (designated M1 and M2) accounted for the remaining radioactivity recovered from urine. The mean concentrations of total radioactivity in whole blood were lower than the concentration observed in plasma, and mean concentrations of THRX-651540 in plasma were minimal relative to mean plasma telavancin concentrations. These observations demonstrate that most of an administered telavancin dose is eliminated unchanged via the kidneys. Intravenous telavancin at 10 mg/kg was well tolerated by all subjects.Telavancin is a once-daily injectable, semisynthetic lipoglycopeptide antibiotic with bactericidal activity in vitro against a broad spectrum of clinically important Gram-positive bacteria including methicillin-resistant Staphylococcus aureus (MRSA), streptococci, and enterococci (4, 5, 9, 10). Telavancin has a dual mode of action, involving inhibition of bacterial cell wall peptidoglycan biosynthesis and disruption of bacterial cell membrane functional integrity (7). In phase 3 trials, telavancin was shown to be noninferior to conventional vancomycin therapy for treatment of complicated skin and skin-structure infections (cSSSIs) and nosocomial pneumonia caused by Gram-positive bacteria and demonstrated an acceptable safety and tolerability profile (13, 15, 16). Telavancin is indicated in the United States and Canada for the treatment of adult patients with cSSSI caused by susceptible Gram-positive bacteria and is under investigation for the treatment of Gram-positive nosocomial pneumonia.Single- and multiple-dose pharmacokinetic parameters for telavancin have been evaluated in phase 1 studies, in which telavancin displayed linear and time-invariant pharmacokinetics following intravenous administration (6, 14, 17). Since telavancin is largely excreted intact in urine along with small amounts of its primary hydroxylated metabolite THRX-651540 (data on file with Theravance, Inc., South San Francisco, CA), renal clearance is thought to be the major route of elimination. The objectives of the present study were to confirm this hypothesis by characterizing the mass balance and pharmacokinetics of single-dose [¹⁴C]telavancin in human subjects.     

Pharmacokinetics of gatifloxacin in infants and children

Gatifloxacin is an 8-methoxy fluoroquinolone effective against a broad spectrum of pathogens common in pediatric infections. The safety and pharmacokinetics of a single dose of gatifloxacin were studied in pediatric patients from 6 months to 16 years of age. Seventy-six pediatric patients (average age, 6.7 +/- 5.0 years) were administered a single oral dose of gatifloxacin suspension (5, 10, or 15 mg/kg of body weight; 600-mg maximum) in a dose-escalating manner. Subjects were stratified by age into 4 groups. An additional 12 children, greater than 6 years of age, received gatifloxacin as the tablet formulation at a dose of approximately 10 mg/kg. Gatifloxacin's apparent clearance and half-life were 5.5 +/- 2.1 ml/min/kg and 5.1 +/- 1.4 h. The maximum concentration of drug in plasma and area under the concentration-time curve (AUC) increased in a manner approximately proportional to the dose. At the 10-mg/kg dose, the bioavailability was similar between the suspension and tablet formulation. The apparent oral clearance of gatifloxacin, normalized for body weight, exhibited a small but statistically significant decrease with increasing age. In all subjects receiving gatifloxacin at 10 mg/kg, the AUC exceeded 20 microg . h/ml (estimated free AUC/MIC ratio of > or =34 for MIC of < or =0.5 microg/ml). These data suggest that gatifloxacin at a dose of 10 mg/kg every 24 h will achieve therapeutic concentrations in plasma in infants and children.     

Comparative pharmacokinetics of aminoglycoside antibiotics in guinea pigs.

The pharmacokinetics of netilmicin, gentamicin, and tobramycin in plasma and in perilymph of guinea pigs were studied after a single intravenous injection of 40 mg/kg. Detailed pharmacokinetic analysis of the plasma drug concentration-time data up to 36 h after the intravenous dose revealed that the pharmacokinetics of the aminoglycoside antibiotics can be best described as a three-compartment open model. The disposition half-lives (t1/2) in plasma of the three antibiotics were comparable and within the following ranges: t1/2 alpha of 0.09 to 0.16 h; t1/2 beta of 0.88 to 1.01 h; and t1/2 gamma of 7.87 to 8.29 h. The volume of distribution in the central compartment and the total body clearance of netilmicin (294 ml/kg, 5.74 ml/min per kg) were greater than those of gentamicin (160 ml/kg, 3.40 ml/min per kg) and tobramycin (204 ml/kg, 4.63 ml/min per kg). Pharmacokinetic analysis of the perilymph drug concentration-time data indicated that all three antibiotics penetrated the perilymph readily, but netilmicin cleared from the perilymph compartment faster than gentamicin and tobramycin. The maximum perilymph drug concentrations were 4.17, 8.05, and 6.78 micrograms/ml and occurred at 1, 2, and 4 h for netilmicin, gentamicin, and tobramycin, respectively. The ratio of area under the curve of perilymph to plasma was lowest for netilmicin (0.27), followed by gentamicin (0.39) and tobramycin (0.57). These results suggest that the differences in pharmacokinetics and concentrations of netilmicin in the perilymph may account for less ototoxic liability of netilmicin compared with gentamicin and tobramycin.     

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.     

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.     

Age-related effects on nelfinavir and M8 pharmacokinetics: a population study with 182 children

As a relationship between nelfinavir antiretroviral efficacy and plasma concentrations has been previously established, nelfinavir pharmacokinetics was investigated in order to optimize the individual treatment schedule in a pediatric population. A population pharmacokinetic model was developed to describe the concentration-time course of nelfinavir and its active metabolite M8. Individual characteristics were used to explain the large interindividual variability in children. Data from therapeutic drug monitoring in 182 children treated with nelfinavir were analyzed with NONMEM. Then Food and Drug Administration (FDA) current recommendations were evaluated estimating the percentage of children who reached the target minimum plasma concentration (0.8 mg/liter) by using Bayesian estimates. Nelfinavir pharmacokinetics was described by a one- compartment model with linear absorption and elimination. Pharmacokinetic estimates and the corresponding intersubject variabilities for the model were as follows: nelfinavir total clearance, 0.93 liters/h/kg (39%); volume of distribution, 6.9 liters/kg (109%); absorption rate, 0.5 h(-1); formation clearance fraction to hydroxy-tert-butylamide (M8), 0.025; M8 elimination rate, 1.88 h(-1) (49%). Apparent nelfinavir total clearance and volume of distribution decreased as a function of age. M8 elimination rate was increased by concomitant administration of nevirapine or efavirenz. Our data confirm that the FDA recommendations for children from 2 to 13 years are optimal and that the dose recommended for children younger than 2 years is adequate for the children from 2 months to 2 years old. However, in children younger than 2 months, the proposed nelfinavir newborn dose of 40 mg/kg of body weight twice daily is inadequate and we suggest increasing the dose to 50 to 60 mg/kg administered thrice daily. This assumption should be further evaluated.     

利奈唑胺在大鼠血、脑组织和脑脊液中的药代动力学研究

目的 探讨利奈唑胺在大鼠血、脑组织和脑脊液中药代动力学特性,为临床治疗中枢神经系统感染提供参考.方法 78只清洁型SD大鼠,尾静脉单次注射利奈唑胺54 mg/kg后,采用高效液相色谱法测定大鼠不同时间点的血、脑组织和脑脊液中利奈唑胺的药物浓度,计算其药代动力学参数.结果 注射后0～19h,利奈唑胺在大鼠的血、脑组织和脑脊液的峰浓度（Cmax）分别为31.39、5.11、23.97 μg/ml;消除半衰期（t1/2）分别为2.67、2.42、1.99 h;药物浓度-时间曲线下面积（AUC 0～∞）分别为134.55、28.23、136.43 h·μg/ml,血脑屏障穿透率为76.36％.结论 利奈唑胺能很好地进入脑脊液达到有效的抑菌浓度,具有良好的药代动力学特征和组织穿透性.     

Pharmacokinetics of trimethoprim and sulfamethoxazole in serum and cerebrospinal fluid of adult patients with normal meninges.

The pharmacokinetics of trimethoprim (TMP) and sulfamethoxazole (SMX) in cerebrospinal fluid (CSF) and serum after a single intravenous infusion of 5 mg of TMP and 25 mg of SMX per kg of body weight over approximately 120 min were studied i nine patients who had uninflamed meninges and were undergoing elective myelography. Peak concentrations of TMP and SMX in CSF were 1 microgram/ml and 13.8 micrograms/ml, respectively. The peak TMP concentration in CSF occurred significantly earlier than the peak SMX concentration (60 versus 480 min postinfusion). At 15 h, there was no detectable TMP in the CSF, and there was 4.7 micrograms of SMX per ml of CSF. In the postdistribution phase (in CSF), simultaneous CSF-to-serum concentration ratios ranged from 0.23 to 0.53 for TMP and from 0.20 to 0.36 for SMX. CSF penetration (measured by comparison of the area under the curve of the composite CSF and serum concentration-time curves) was 18% for TMP and 12% for SMX. A loading dose of TMP-SMX (bases on TMP) of 10 to 12 mg/kg and a maintenance dose of 6 mg/kg every 8 h or 8 mg/kg every 12 h (with a 2-h infusion) should yield steady-state peak concentrations of at least 5 micrograms of TMP per ml of serum and 160 micrograms of SMX per ml of serum. Further studies of TMP-SMX administered in these doses in the treatment of serious bacterial infection, including meningitis, are warranted.