E. Rey

Pharmacokinetics of midazolam in children: comparative study of intranasal and intravenous administration

SummaryTwelve children 1–5 y old were randomly assigned to receive midazolam 0.2 mg·kg−1 either by the intravenous (IV) or intranasal (IN) routes.After IN administration the rapid onset of absorption was observed (tmax 12 min). After both routes of administration the half-life was similar (2.2 h IN and 2.4 h IV). After IN administration the apparent plasma clearance and volume of distribution were about twice as high as after IV administration.The results are consistent with an estimated mean bioavailability of 55%.

Population Pharmacokinetics of Tenofovir in HIV-1-Infected Pregnant Women and Their Neonates (ANRS 12109)

Thirty‐eight human immunodeficiency virus‐1 (HIV‐1)‐infected pregnant women were administered tenofovir disoproxil fumarate (TDF; 300 mg)–emtricitabine (FTC; 200 mg) tablets: two at labor initiation and one daily for 7 days postpartum. Maternal, umbilical, and neonatal plasma tenofovir concentrations were measured by high‐performance liquid chromatography and analyzed using a population approach. Data were described using a two‐compartment model for the mother, an effect compartment linked to maternal circulation for cord, and a neonatal compartment disconnected after delivery. Absorption was greater for women delivering by caesarian section than for those delivering vaginally. The maternal 600 mg TDF administration before delivery produces the same concentrations as 300 mg administration in other adults. If the time elapsed between maternal administration and delivery is ≥12 h, two tablets of TDF–FTC should be readministered. Tenofovir showed good placental transfer (60%). Administering 13 mg/kg of TDF as soon as possible after birth should produce neonatal concentrations comparable with those observed in adults.

Quantification of seven nucleoside/nucleotide reverse transcriptase inhibitors in human plasma by high-performance liquid chromatography with tandem mass-spectrometry

A simple analytical method was developed in 100 microL of plasma for the simultaneous assay of the 7 nucleoside/nucleotide reverse transcriptase inhibitors (abacavir, didanosine, emtricitabine, lamivudine, stavudine, tenofovir, and zidovudine) currently used for the treatment of HIV-infected patients. After adding the internal standard, 6-beta-hydroxy-theophyline, plasma samples were precipitated with 500 microL acetonitrile and the supernatants were evaporated to dryness. The residues were reconstituted with 500 microL of water and 10 microL of the extracts were injected in the chromatographic system. The chromatographic separation was performed with a C-18 column and a gradient mobile phase consisting of a mixture of water and acetonitrile, both containing 0.05% formic acid. Analytes quantification was performed by electrospray ionisation triple quadrupole mass-spectrometry in the positive mode using selected reaction monitoring (SRM). Intra- and inter-assay precision and accuracy were lower than 20% for the limit of quantification, and 15% for higher concentrations. The method has been implemented to assess plasma concentrations of patients infected by HIV and was found suitable for therapeutic drug monitoring.

Simultaneous determination of three carbapenem antibiotics in plasma by HPLC with ultraviolet detection

A simple, precise and accurate high-performance liquid chromatography (HPLC) method using ultraviolet (UV) detection has been developed for simultaneous determination of carbapenem antibiotics: imipenem, meropenem and ertapenem in human plasma. Samples were spiked with ceftazidime as internal standard and proteins were precipitated by acetonitrile. Separation was achieved on a C8 column with a mobile phase composed of phosphate buffer 0.1M (pH 6.8) and methanol in gradient elution mode. Detection was performed at 298 nm. Calibration curves were linear from 0.5 to 80 mg/L for each compound, with correlation coefficients over 0.997. Intra- and inter-day validation studies showed accuracy between -4.5 and 8.1% and precision below 10.4%. Mean recoveries were 82.2, 90.8 and 87.7% for imipenem, meropenem and ertapenem, respectively. This method provides a useful tool for the therapeutic drug monitoring of carbapenems.

Nonparametric Population Pharmacokinetic Analysis of Amikacin in Neonates, Infants, and Children

ABSTRACT The therapeutic and toxic effects of amikacin are known to depend on its concentration in plasma, but the pharmacokinetics of this drug in neonates, infants, and children and the influences of clinical and biological variables have been only partially assessed. Therapeutic drug monitoring data collected from 155 patients (49 neonates, 77 infants, and 29 children) receiving amikacin were analyzed by a nonparametric population-based approach, the nonparametric maximum-likelihood method. We assessed the effects of gestational and postnatal age, weight, Apgar score, and plasma creatinine and urea concentrations on pharmacokinetic parameters. There is no specific formulation of amikacin for neonates and infants. We therefore used an error model to account for errors due to dilution during preparation of the infusion. The covariates that reduced the variance of clearance from plasma and the volume of distribution by more than 10% were postnatal age (43 and 28%, respectively) and body weight (30.4 and 17.4%, respectively). The expected reduction of clearance was about 10% for the plasma creatinine concentration. The other covariates studied (Apgar scores, plasma urea concentration, gestational age, sex) were found to have little effect. Simulations showed that a smaller percentage of patients had a maximum concentration in plasma/MIC ratio greater than 8 with a regimen of 7.5 mg/kg of body weight twice daily than with a regimen of 15 mg/kg once a day for MICs of 1 to 8 mg/liter.

Pharmacokinetics of Clorazepate in Pregnant and Non-Pregnant Women

SummaryA single dose of clorazepate 20 mg was injected i.m. in 7 pregnant and 7 non-pregnant women. Blood samples were collected for one week, and urine was collected for 24 h after the dose. The concentrations of clorazepate and its metabolite nordiazepam were determined by electron capture gas liquid chromatography. There was no difference between the two groups on physical examinations. Clorazepate was rapidly absorbed and the peak concentration was reached within 2h. Mean pharmacokinetic parameters for clorazepate were absorption half life 0.77h in pregnant women and 0.56h in non-pregnant women; elimination half life 1.3h in pregnant women and 2.0h in non-pregnant women; volume of distribution: 0.43 l · kg−1 in the pregnant women and 0.33 l · kg−1 in non-pregnant women. Nordiazepam reached its peak concentration within 12h after dosing; its mean half life of elimination was 180h in pregnant women and 60h in non-pregnant women. Within 24h, 1.3% of the clorazepate was recovered in urine from pregnant women and 7% in urine from the non-pregnant women.

Effect of stiripentol on carbamazepine plasma concentration and metabolism in epileptic children

Objective: To study the relationship between the plasma concentration of stiripentol (STP), a new antiepileptic drug, and its inhibitory effect on the formation of carbamazepine epoxide (CBZE) in epileptic children treated with carbamazepine (CBZ) either alone or in combination with another antiepileptic drug.Methods:Minimum plasma concentration of antiepileptic drugs was measured before initiation of STP therapy (day 0) and on days 28 (STP 60 mg⋅kg−1⋅day−1) and 84 (STP 90 mg⋅kg−1⋅day−1) by HPLC.Results:The CBZE/CBZ plasma concentration ratio decreased exponentially with increasing minimum plasma STP concentration (r = 0.80). The asymptote of the curve allowed the calculation of the minimum plasma STP concentration required to obtain the maximum inhibitory effect, i.e. 6.7 mg⋅l−1.Conclusion:The inhibitory effect of STP on CBZ metabolism expressed as the CBZE/CBZ plasma concentration ratio is dependent on STP plasma concentration, with a maximum effect at an average of 7 mg⋅l−1. The present data suggest that in order to evaluate the anticonvulsant efficacy of STP as add-on therapy, the minimum plasma STP concentration should be maintained above 7 mg⋅l−1 and the dosage of CBZ should simultaneously be decreased in steps by more than 50% to minimize the change in CBZ plasma concentration.

Population pharmacokinetics of nevirapine in HIV-1-infected pregnant women and their neonates.

ABSTRACT The aim of the present study was to describe the nevirapine (NVP) pharmacokinetics (PK) in pregnant women and their neonates and to evaluate the transplacental drug transfer and administration scheme for the prevention of mother-to-child transmission. Thirty-eight HIV-1-infected pregnant women were administered one tablet of NVP (200 mg) and two tablets of tenofovir-emtricitabine (Truvada) at the initiation of labor. Children were given NVP syrup (2 mg/kg of body weight) as a single dose (sdNVP) on the first day of life. By pair, NVP concentrations were measured in 11 maternal, 1 cord blood, and 2 neonatal plasma samples and analyzed by a population approach. A one-compartment model was used for mothers and neonates; the absorption rate constants for mothers and neonates were 0.95 h−1 (intersubject variability, 111%) and 0.39 h−1, respectively; the apparent elimination clearances were 1.42 liter·h−1 (intersubject variability, 22%) and 0.035 liter·h−1, respectively; and apparent volumes of distribution were 87.3 liters (intersubject variability, 25%) and 5.65 liters, respectively. An effect compartment was linked to maternal circulation by mother-to-cord and cord-to-mother rate constants of 1.10 h−1 and 1.43 h−1, respectively. Placental transfer, expressed as the fetal-to-maternal area under the curve ratio, was 75%. Neonates had a very long half-lives (110 h) compared to adults. In the 38 mothers, the simulated median individual predicted time during which the NVP concentration remained above the half-maximal inhibitory concentration (IC50) was 13.2 days (range, 12 to 19.2 days). Thus, the administration of tenofovir-emtricitabine for at least 3 weeks after delivery should be considered to prevent the emergence of resistant viruses. The neonate must receive sdNVP immediately after birth when the infant is born less than 30 min after maternal drug intake to keep NVP concentrations above the IC50.

Pharmacokinetics of the placental transfer and distribution of clorazepate and its metabolite nordiazepam in the feto-placental unit and in the neonate.

SummaryClorazepate 20mg was given i. m. to 49 mothers during the first stage of labour. The elimination of the drug was studied in 27 newborns produced by these mothers. The same dose was given to 13 women who underwent amniocentesis and to 7 women who were breast-feeding. “Total nordiazepam”, i.e. the sum of clorazepate and its metabolite nordiazepam, was determined by gas-liquid chromatography in maternal blood, umbilical cord blood (both arterial and venous), amniotic fluid and in milk. Clorazepate was found to cross the placental barrier slowly, but nordiazepam was transferred more rapidly. Nordiazepam was found in the milk and in the blood of neonates after breast-feeding had started.

Joint Population Pharmacokinetic Analysis of Zidovudine, Lamivudine, and Their Active Intracellular Metabolites in HIV Patients

ABSTRACT The population pharmacokinetic parameters of zidovudine (AZT), lamivudine (3TC), and their active intracellular metabolites in 75 naïve HIV-infected patients receiving an oral combination of AZT and 3TC twice daily as part of their multitherapy treatment in the COPHAR2-ANRS 111 trial are described. Four blood samples per patient were taken after 2 weeks of treatment to measure drug concentrations at steady state. Plasma AZT and 3TC concentrations were measured in 73 patients, and among those, 62 patients had measurable intracellular AZT-TP and 3TC-TP concentrations. For each drug, a joint population pharmacokinetic model was developed and we investigated the influence of different covariates. We then studied correlations between the mean plasma and intracellular concentrations of each drug. A one-compartment model with first-order absorption and elimination best described the plasma AZT concentration, with an additional compartment for intracellular AZT-TP. A similar model but with zero-order absorption was found to adequately described concentrations of 3TC and its metabolite 3TC-TP. The half-lives of AZT and 3TC were 0.81 h (94.8%) and 2.97 h (39.2%), respectively, whereas the intracellular half-lives of AZT-TP and 3TC-TP were 10.73 h (69%) and 21.16 h (44%), respectively. We found particularly a gender effect on the apparent bioavailability of AZT, as well as on the mean plasma and intracellular concentrations of AZT, which were significantly higher in females than in males. Relationships between mean plasma drug and intracellular metabolite concentrations were also highlighted both for AZT and for 3TC. Simulation with the model of plasma and intracellular concentrations for once- versus twice-daily regimens suggested that a daily dosing regimen with double doses could be appropriate.