Christophe Padoin

Clinical pharmacokinetics of diacerein.

Diacerein is a drug for the treatment of patients with osteoarthritis. This drug is administered orally as 50mg twice daily. Diacerein is entirely converted into rhein before reaching the systemic circulation. Rhein itself is either eliminated by the renal route (20%) or conjugated in the liver to rhein glucuronide (60%) and rhein sulfate (20%); these metabolites are mainly eliminated by the kidney.The pharmacokinetics characteristics of diacerein are about the same in young healthy volunteers and elderly people with normal renal function, both after a single dose (50mg) or repeated doses (25 to 75mg twice daily). Rhein kinetics after single oral doses of diacerein are linear in the range 50 to 200mg. However, rhein kinetics are time-dependent, since the nonrenal clearance decreases with repeated doses. This results in a moderate increase in maximum plasma concentration, area under the plasma concentration-time curve and elimination half-life. Nevertheless, the steady-state is reached by the third administration and the mean elimination half-life is then around 7 to 8 hours.Taking diacerein with a standard meal delays systemic absorption, but is associated with a 25% increase in the amount absorbed. Mild-to-severe (Child Pugh’s grade B to C) liver cirrhosis does not change the kinetics of diacerein, whereas mild-to-severe renal insufficiency (creatinine clearance <2.4 L/h) is followed by accumulation of rhein which justifies a 50% reduction of the standard daily dosage.Rhein is highly bound to plasma proteins (about 99%), but this binding is not saturable so that no drug interactions are likely to occur, in contrast to those widely reported with nonsteroidal anti-inflammatory drugs. Except for moderate and transient digestive disturbances (soft stools, diarrhoea), diacerein is well tolerated and seems neither responsible for gastrointestinal bleeding nor for renal, liver or haematological toxicity.

Individualising aminoglycoside dosage regimens after therapeutic drug monitoring: simple or complex pharmacokinetic methods?

Measurements of aminoglycoside concentration in serum are used to individualise dosage regimens (dose per administration and/or administration interval) with the goal of attaining the desired therapeutic range as quickly as possible. Therapeutic range is defined in terms of peak concentration (to monitor effectiveness) and trough concentration (to avoid toxicity). This article focuses on methods to individualise aminoglycoside dosage regimens in the context of extended dosage intervals.Simple pharmacokinetic methods involve linear dosage adjustment based on peak or trough concentrations or area under the concentration-time curve, or nomograms. The once daily aminoglycoside nomogram determines the dosage interval for aminoglycosides given as a fixed dose per administration, based on a single concentration measurement drawn 6 to 14 hours after the start of the first infusion. This is a preferred method because of its simplicity, strong pharmacodynamic rationale and prospective validation in a large population. However, it does not work when the fixed dose assumed is not relevant, for example for patients with burns, cystic fibrosis, ascites or pregnancy. Furthermore, it has not been validated in children. In these cases, a more sophisticated method is required.Complex pharmacokinetic methods require dedicated software. Non-Bayesian least-squares methods allow the optimisation of both the dose and the dosage interval, but require aminoglycoside concentrations from two or more samples taken in the post-distributive phase during a single dosage interval. With Bayesian least-squares methods, only one concentration measurement is required, although any number of samples can be taken into account. In the Bayesian maximum a posteriori (MAP) method, the parameter estimates are taken as the values corresponding to the maximum of the posterior density. In ‘full’ Bayesian approaches (also called stochastic control), all the information about the parameters revealed by the posterior distribution is taken into account, and the optimal regimen is found by minimising the expected value of the weighted sum of squared deviations between predicted and target concentrations.If the population model is reasonably well known, Bayesian methods (MAP or stochastic control) should be used because of their good predictive performance. Although only one concentration measurement is required, better precision is afforded by a two-sample strategy, preferably drawn 1 and 6 hours after the start of the first infusion. If the population model is not known, then the non-Bayesian least-squares method is the method of choice, because of its robustness and lack of requirement for prior information about the distribution of parameters in the population.

Clinical pharmacokinetics and pharmacodynamics of isepamicin.

Isepamicin is an aminoglycoside antibacterial with properties similar to those of amikacin, but with better activity against strains producing type I 6′-acetyltransferase. The antibacterial spectrum includes Enterobacteriaceae and staphylococci. Anaerobes, Neisseriaceae and streptococci are resistant. The lower and upper break-points are 8 and 16 mg/L. Like other aminoglycosides, isepamicin exhibits a strong concentration-dependent bactericidal effect, a long post-antibiotic effect (several hours) and induces adaptive resistance.Isepamicin is administered intravenously or intramuscularly at a dosage of 15 mg/kg once daily or 7.5 mg/kg twice daily. Isepamicin is not bound to plasma proteins, and it distributes in extracellular fluids and into some cells (outer hair cells, kidney cortex) by active transport. Isepamicin is not metabolised and is eliminated solely via the renal route with an elimination half-life (t½,β) of 2 to 3 hours in adults with normal renal function. The clearance of isepamicin is reduced in neonates, and 7.5 mg/kg once daily is recommended in children <16 days old. Clearance is also reduced in the elderly, but no dosage adjustment is required. In patients with chronic renal impairment, isepamicin clearance is proportional to creatinine clearance (CLCR); the recommended regimen is 8 mg/kg with an administration interval of 24 hours in moderate impairment, 48 hours in severe impairment, 72 hours for CLCR 0.6 to 1.14 L/h (10 to 19 ml/min) and 96 hours for CLCR 0.36 to 0.54 L/h (6 to 9 ml/min). In end-stage renal failure, isepamicin is eliminated by haemodialysis, but the administration interval should be determined by monitoring the plasma concentration.Compared with healthy volunteers, patients in the intensive care unit or with neutropenic cancer have an increased volume of distribution and a lower clearance, but the 15 mg/kg once daily regimen remains adequate. Isepamicin kinetics are linear in the range 7.5 to 25 mg/kg, so that dosage adjustments, if necessary, are straightforward. Isepamicin can induce nephro-, vestibulo- and oto-toxicity. However, animal and clinical studies show that isepamicin is one of the less toxic aminoglycosides.The usefulness of maintaining serum aminoglycoside concentrations within a therapeutic range remains controversial. With isepamicin, it is proposed to achieve a 1-hour concentration (30 minutes after a 30-minute infusion) >40 mg/L to maximise bactericidal efficacy, and a ‘trough’ concentration (at the end of the administration interval) <5 mg/L to minimise toxicity. These thresholds should be modified on an individual basis, considering covariates such as concomitant treatment, underlying disease, nature of bacterial strain and site of infection.

Ceftriaxone pharmacokinetics during iatrogenic hydroxyethyl starch-induced hypoalbuminemia: a model to explore the effects of decreased protein binding capacity on highly bound drugs.

BACKGROUND Although various drugs used by anesthesiologists highly bind to plasma proteins, the impact of iatrogenically induced hypoproteinemia on their pharmacologic effects has never been investigated. The authors determined the pharmacokinetics of ceftriaxone, a cephalosporin that binds strongly to albumin in postsurgical patients with hydroxyethyl starch-induced hypoalbuminemia. METHODS Eleven hypoalbuminemic (serum albumin < 25 g/l) patients and age (+/- 5 yr)-, sex-, and body surface area (+/- 10%)-matched healthy volunteers received a 2-g ceftriaxone dose infused over a 15-min period. Fourteen venous blood samples were collected during the 24-h study period. Free ceftriaxone concentrations were determined by ultrafiltration. Antibiotic concentrations in plasma and ultrafiltrate were measured by ion-paired reversed-phase chromatography. The pharmacokinetic parameters derived from total and free antibiotic concentrations were determined using a noncompartmental method. Data are expressed as median and range. RESULTS The pharmacokinetic parameters derived from total ceftriaxone concentrations were similar for the two groups, except for the median corrected volume of distribution at steady state, which was increased (P = 0.05) to 0.18 l/kg (range, 0. 11-0.29 l/kg) in patients, compared with 0.15 l/kg (range, 0.13-0.22 l/kg) in volunteers. The area under the free ceftriaxone concentration-time curve was twice as high in patients as in volunteers (median 192, range 114-301 vs. median 122, range 84-169 h. mg-1. l-1;P = 0.03). Moreover, the free ceftriaxone concentration remained more than 4 mg/l during more time in patients (median, 16. 7; range, 12.6-21.4 vs. median, 11.1; range, 6.0-19.0 h; P = 0.03). CONCLUSIONS Compared with healthy volunteers, patients with iatrogenic hypoalbuminemia have higher free ceftriaxone concentrations during the 24 h after antibiotic administration. This modification increases drug distribution into extravascular space and may enhance effectiveness.

Sensitive and rapid method for the simultaneous quantification of the HIV-protease inhibitors indinavir, nelfinavir, ritonavir, and saquinavir in human plasma by reversed-phase liquid chromatography

A rapid, sensitive, and specific liquid chromatography method for the simultaneous determination of four protease inhibitors (indinavir, nelfinavir, ritonavir, and saquinavir) in human plasma is described. After a liquid-liquid extraction with terbutyl methyl ether and a sequential washing of the reconstituted sample with hexane, protease inhibitors are separated on a phenyl column using a simple binary mobile phase of ammonium acetate buffer:acetonitrile (48:52) (pH = 7.5) with an ultraviolet detection at 260 nm. The standard curves are linear in the range 0.025–1 &mgr;g/mL for saquinavir, 0.1–4 &mgr;g/mL for indinavir and nelfinavir, and 0.25–10 &mgr;g/mL for ritonavir, with an average recovery ranging from 79% to 99%, and with both low interday and intraday coefficients of variation (<15%). This assay is simple, rapid (15-minute interval between runs) , and useful for therapeutic monitoring of the protease inhibitors on a routine basis.

Efficacies of Imipenem, Meropenem, Cefepime, and Ceftazidime in Rats with Experimental Pneumonia Due to a Carbapenem-Hydrolyzing β-Lactamase-Producing Strain of Enterobacter cloacae

ABSTRACT The antibacterial activities of imipenem-cilastatin, meropenem-cilastatin, cefepime and ceftazidime againstEnterobacter cloacae NOR-1, which produces the carbapenem-hydrolyzing β-lactamase NmcA and a cephalosporinase, and against one of its in vitro-obtained ceftazidime-resistant mutant were compared by using an experimental model of pneumonia with immunocompetent rats. The MICs of the β-lactams with an inoculum of 5 log10 CFU/ml were as follows for E. cloacae NOR-1 and its ceftazidime-resistant mutant, respectively: imipenem, 16 and 128 μg/ml, meropenem, 4 and 32 μg/ml, cefepime, <0.03 and 1 μg/ml, and ceftazidime, 1 and 512 μg/ml. The chromosomally located cephalosporinase and carbapenem-hydrolyzing β-lactamase NmcA were inducible by cefoxitin and meropenem inE. cloacae NOR-1, and both were stably overproduced in the ceftazidime-resistant mutant. Renal impairment was induced (uranyl nitrate, 1 mg/kg of body weight) in rats to simulate the human pharmacokinetic parameters for the β-lactams studied. Animals were intratracheally inoculated with 8.5 log10 CFU of E. cloacae, and therapy was initiated 3 h later. At that time, animal lungs showed bilateral pneumonia containing more than 6 log10 CFU of E. cloacae per g of tissue. Despite the relative low MIC of meropenem for E. cloacae NOR-1, the carbapenem-treated rats had no decrease in bacterial counts in their lungs 60 h after therapy onset compared to the counts for the controls, regardless of whether E. cloacae NOR-1 or its ceftazidime-resistant mutant was inoculated. A significant decrease in bacterial titers was observed for the ceftazidime-treated rats infected with E. cloacae NOR-1 only. Cefepime was the only β-lactam tested effective as treatment against infections due to E. cloacae NOR-1 or its ceftazidime-resistant mutant.

Application of optimal sampling theory to the determination of metacycline pharmacokinetic parameters : effect of model misspecification

Use of optimal sampling theory (OST) in pharmacokinetic studies allows the number of sampling times to be greatly reduced without loss in parameter estimation precision. OST has been applied to the determination of the bioavailability parameters (area under the curve (AUC), maximal concentration (Cmax), time to reach maximal concentration (Tmax), elimination half-life (T1/2), of metacycline in 16 healthy volunteers. Five different models were used to fit the data and to define the optimal sampling times: one-compartment first-order, two-compartment first-order, twocompartment zero-order, two-compartment with Michaelis-Menten absorption kinetics, and a stochastic model. The adequacy of these models was first evaluated in a 6-subject pilot study. Only the stochastic model with zero-order absorption kinetics was adequate. Then, bioavailability parameters were estimated in a group of 16 subjects by means of noncompartmental analysis (with 19 samples per subject) using each optimal sampling schedule based procedure (with 6 to 9 samples depending on the model). Bias (PE) and precision (RMSE) of each bioavailability parameter estimation were calculated by reference to noncompartmental analysis, and were satisfactory for the 3 adequate models. The most relevant criteria for discrimination of the best model were the coefficient of determination, the standard deviation, and the mean residual error vs. time plot. Additional criteria were the number of required sampling times and the coefficient of variation of the estimates. In this context, the stochastic model was superior and yielded very good estimates of the bioavailability parameters with only 8 samples per subject.

Tenofovir DF/emtricitabine and efavirenz combination therapy for HIV infection in patients treated for tuberculosis: the ANRS 129 BKVIR trial.

BACKGROUND HIV-infected patients with TB need simplified, effective and well-tolerated antiretroviral regimens. METHODS The French ANRS 129 BKVIR open trial evaluated the once-daily tenofovir DF/emtricitabine and efavirenz combination, started within 12 weeks after TB treatment initiation, in antiretroviral-naive HIV-1-infected patients. Success was defined as an HIV-1 RNA <50 copies/mL and TB cure at 48 weeks. RESULTS TB was confirmed microbiologically (90%) or histologically (10%) in 69 patients (71% male; median age 43 years; 54% born in Africa). The median time between TB treatment initiation and antiretroviral therapy was 8 weeks (range 1-22 weeks). At baseline, median HIV-1 RNA was 5.4 log10 copies/mL and median CD4 cell count 74 cells/mm(3). In the ITT analysis, combined success at week 48 was achieved in 57/69 patients (83%, 95% CI 74-92). Twelve patients did not achieve virological success, and TB was not cured in one of them. Among the 47 patients who fully adhered to the strategy, the success rate was 96% (95% CI 90-100) and was not affected by low rifampicin and isoniazid serum concentrations. Forty-nine serious adverse events were reported in 31 patients (45%), and 11 led to antiretroviral drug interruption. All adverse events resolved. The immune reconstitution inflammatory syndrome occurred in 23 patients (33%, 95% CI 22-44), and was associated with a low baseline BMI (P = 0.03) and a low haemoglobin level (P = 0.02). CONCLUSION These results support the use of tenofovir DF/emtricitabine and efavirenz combination therapy for HIV infection in patients with TB.