Marc Galtier

Cisplatin-induced renal toxicity and toxicity-modulating strategies: a review

Cisplatin, or cis-diamminedichloroplatinum(II) (CDDP), is an antineoplastic agent developed in 1965 by Rosenberg et al. [70], who were studying the effects of electrolysis products from a platinum electrode on growing cells. Cisplatin was clinically tested in 1972 by Hill et al. [40]. In spite of its good antineoplastic activity against ovarian, lung, bladder, breast, head and neck.~ and testicular cancer, its clinical use was rapidly limited due to unexpected and very severe renal toxicity. Acute and cumulative renal toxicity associated with histological damage has been shown in both animal and human studies. Several theories concerning the pathophysiological mechanism behind this toxicity have been suggested [13, 59]. Since the therapeutic efficacy of cisplatin seems to be proportional to the delivered dose [80], there has been a continuous search for biological and pharmacological strategies to protect the renal function and thus permit the administration of high quantities of the drug; these strategies include modification of administration modes, development of new galenic forms, and the use of chemoprotectors, among others. Additionally, other platinum analogs with less nephrotoxicity have been studied, but these agents have less antitumor activity than cisplatin or have other inherent toxicities restricting their use [78].

Clinical Pharmacokinetics During Continuous Haemofiltration

SummaryContinuous haemofiltration is an extracorporeal technique that is increasingly used to remove fluid, electrolytes, and other waste products from the blood supply of critically ill patients with acute renal failure. Continuous arteriovenous haemofiltration (CAVH), where the blood exits the body from an artery and re-enters through a vein, is widely used. Continuous venovenous haemofiltration (CVVH), where blood both exits and enters through a vein by way of a mechanical pump, avoids problems that result from the variable ultrafiltration rate found during CAVH. Continuous arteriovenous or venovenous haemodiafiltration (CAVHD or CVVHD) combine continuous haemofiltration and haemodialysis.All methods involve ultrafiltration of the patient’s blood through a filter that is highly permeable to water and small molecules. Drug elimination by haemofiltration depends mainly on the rate of ultrafiltration, the drug protein binding and the sieving coefficient of the membrane. Because patients undergoing continuous haemofiltration have impaired renal function, dosage reduction is often recommended so that adverse drug reactions are avoided. In contrast, if drug removal by haemofiltration is significant, dosage supplementation may be required to ensure therapeutic efficacy of the drug. Therefore, knowledge of the impact of continuous haemofiltration on drug elimination and the pharmacokinetic profile of drugs is essential to good clinical management.The currently available information on the clinical pharmacokinetic aspects of drug therapy during continuous haemofiltration are summarised. Drugs commonly associated with haemofiltration therapy are tabulated with updated pharmacokinetics and drug-monitoring information.

Endotracheal and aerosol administrations of ceftazidime in patients with nosocomial pneumonia: pharmacokinetics and absolute bioavailability.

Pharmacokinetic studies on ceftazidime, an aminothiazole cephalosporin with a wide spectrum of antibacterial activity, including activity against Pseudomonas aeruginosa, were performed in patients with nosocomial pneumonia. The concentration-time profiles of ceftazidime in plasma, urine, and bronchial secretions of 12 patients were investigated after intravenous (i.v.) (n = 12), endotracheal (n = 10), and aerosol (n = 5) administrations. In all cases a 1-g dose was administered. Concentrations of drug in all samples were assayed by high-performance liquid chromatography with UV detection. The elimination of the drug from the blood followed a biexponential (i.v. administration) or a monoexponential (endotracheal and aerosol administrations) decay, with an elimination half-life of 6 h and a total body clearance of 4.2 liters/h. The apparent volume of distribution was 0.36 liter/kg of body weight. Renal clearance of the drug accounted for 58% of the total clearance; 66% +/- 17.7%, 33.5% +/- 17.3%, and 6.59% +/- 3.45% of the administered dose were eliminated in urine as parent drug after i.v., endotracheal, and aerosol administrations, respectively. The absolute bioavailabilities were 0.47 and 0.08 for endotracheal and aerosol administrations, respectively. Very high concentrations were found in bronchial secretions after local administration. The MICs for 90% of the most important pathogens responsible for nosocomial infections were exceeded by concentrations in bronchial secretion for up to 12 h after i.v. infusion and for up to 24 h after endotracheal and aerosol administrations.

Doxorubicin and doxorubicinol : intra- and inter-individual variations of pharmacokinetic parameters

SummaryDoxorubicin was given by short i. v. infusion (dose range 25–72 mg/m2) to 18 patients who underwent three to seven successive courses of chemotherapy (total, 57 courses). Plasma levels of doxorubicin and its major metabolite doxorubicinol were determined by high-performance liquid chromatography over a 48-h period after the infusion. Pharmacokinetic parameters for the parent drug and its metabolite were calculated for each course of treatment. The results show considerable inter-and intraindividual variations for most parameters. The coefficients of variation (CV) ranged from 37% to 93% (inter-individual) and from 6% to 59% (intra-individual). Nevertheless, we observed a good stability over successive courses for terminal half-life in six patients (CV, 6%–25%) and for clearance and AUC in four subjects (CV, 10%–22%). The ratio of the AUCs for doxorubicinol: doxorubicin averaged 0.514. The pharmacokinetic pattern of doxorubicinol was biphasic in plasma of the majority of patients. We propose a model for curve-fitting of these metabolite plasma concentrations that is based on two successive releases of the compound in the plasma compartment, separated by a lag time.

Steady-state pharmacokinetics of ciprofloxacin in plasma from patients with nosocomial pneumonia: penetration of the bronchial mucosa.

A 30-min intravenous (i.v.) infusion of 200 mg of ciprofloxacin was administered twice daily to 12 patients with nosocomial pneumonia scheduled to undergo diagnostic fiberoptic bronchoscopy. The pharmacokinetics of ciprofloxacin were examined at the presumed steady state after 5 days of treatment. Eleven successive plasma samples were collected in the interval from 0 to 12 h after administration, and bronchial mucosa samples were taken 2 h after administration. Concentrations of drug in all samples were assayed by high-performance liquid chromatography with fluorimetric detection. The results showed that the kinetics in plasma did not differ from those determined previously in healthy volunteers. The mean concentrations in plasma peaked at 4.94 +/- 2.90 mg/liter at the end of infusion. The terminal half-life was 4.95 +/- 2.81 h, and the mean residence time 6.13 +/- 3.17 h. A large volume of distribution was calculated: 2.59 +/- 1.43 liters/kg. Mean total body clearance was 23.3 +/- 10.1 liters/h. The concentrations in bronchial mucosa reached 21.6 +/- 5.63 micrograms/g 2 h after drug intake. The tissue-versus-plasma concentration ratios ranged from 10.1 to 26.3 (mean value, 16.9 +/- 5.43). After 6 to 12 days of i.v. treatment, four patients were switched to oral ciprofloxacin. We propose a model for the simultaneous fit of the concentration-time curves obtained after i.v. infusion and oral dosing. The concentrations in tissue observed in this study were in excess of the MICs for bacteria considered to be susceptible to ciprofloxacin.

Identification of Patients with Impaired Hepatic Drug Metabolism Using a Limited Sampling Procedure for Estimation of Phenazone (Antipyrine) Pharmacokinetic Parameters

SummaryPhenazone (antipyrine) 1g was given by short intravenous infusion to 62 study participants (10 healthy drug-free volunteers and 52 patients with chronic liver disease). A Bayesian approach was developed to determine the individual pharmacokinetic parameters of Phenazone.Statistical characteristics of the population pharmacokinetic parameters were first evaluated for 30 patients. When combined with 1 plasma drug concentration from members of the second group, these led to a Bayesian estimation of individual pharmacokinetic parameters for the remaining 32 individuals. Total clearance computed by Bayesian estimation was compared with maximal likelihood estimation of this parameter, the classical procedure. No statistically significant differences were found. Performance of the developed methodology was evaluated by computing bias and precision. The mean error was 0.0477 L/h. The precision of the prediction of this parameter (0.155 L/h) remained lower than the interindividual standard deviation (0.765 L/h).This procedure enables the estimation of individual pharmacokinetic parameters for Phenazone. In this study, numerous laboratory tests were performed. A highly significant correlation (p < 0.001) was found between Phenazone clearance and the prothrombin time, albumin, γ-globulin, factor V, antithrombin III, fibrinogen and total bilirubin. Discriminant analysis determined that protein, alkaline phosphatase, creatininaemia and γ-globulin had more significant discriminating power and gave better prognostic results than those seen with the Child-Pugh test.

Pefloxacin Clinical Pharmacokinetics

SummaryPefloxacin has a broad spectrum of activity against a great number of Gram-negative and Gram-positive bacteria. It is also capable of penetration into cells, yielding high tissue: serum ratios, with implications for the treatment of infections caused by intracellular pathogens. Pefloxacin is well absorbed from the gastrointestinal tract. Its elimination half-life ranges from 6.2 to 12.4 hours. After repeated administration, a major change in pharmacokinetic parameters is observed.Pharmacokinetic parameters are minimally altered or not altered in patients with impaired renal function. Altered plasma pharmacokinetics in patients with liver insufficiency and in elderly patients are observed, so dosage adjustments are necessary. In addition, pefloxacin interacts with a number of other compounds at hepatic (e.g. theophylline and cimetidine) and gastrointestinal (e.g. antacids) sites.With the exception of saliva, cerebrospinal fluid, aqueous humor, vitreous fluid and amniotic fluid, body fluid concentrations reach plasma concentrations. Studies on tissue penetration show that concentrations exceeding plasma concentrations are obtained in most tissues. The highest tissue: plasma concentration ratios are achieved in lung and kidney, whereas concentrations in fat are considerably lower than those in plasma.

Multiple-dose pharmacokinetics of amikacin and ceftazidime in critically ill patients with septic multiple-organ failure during intermittent hemofiltration.

The pharmacokinetic parameters of amikacin and ceftazidime were assessed in four patients undergoing hemofiltration for septic shock. The parameters were assessed during hemofiltration and in the interim period. The concentration-time profiles of these two drugs in plasma, urine, and ultrafiltrate were investigated after intravenous perfusion (30 min). In all cases a 1-g dose of ceftazidime was administered; for amikacin, the dosage regimen was adjusted according to the patients amikacin levels (250 to 750 mg). Concentrations of drug in all samples were assayed by high-performance liquid chromatography with UV detection for ceftazidime and by enzyme multiplied immunoassay for amikacin. The elimination half-life (t1/2) and the total clearance of amikacin ranged from 31.1 to 138.2 h and from 5.4 to 8.9 ml/min, respectively, during the interhemofiltration period in anuric patients. Hemofiltration substantially decreased the t1/2 (3.5 +/- 0.49 h) and increased the total clearance (89.5 +/- 11.8 ml/min). The hemofiltration clearance of amikacin represented 71% of the total clearance, and the hemofiltration process removed, on average, 60% of the dose. During hemofiltration, the elimination t1/2 of ceftazidime (2.8 +/- 0.69 h) was greatly reduced and the total clearance increased (74.2 +/- 11.2 ml/min) compared with those in the interhemofiltration period (9 to 43.7 h and 7.4 to 16.8 ml/min, respectively). About 55% of the administered dose was recovered in the filtrate, and the hemofiltration clearance of ceftazidime was 46 +/- 14.3 ml/min. A redistribution phenomenon (rebound) in the amikacin and ceftazidime concentrations in plasma (35 and 28%, respectively) was reported after hemofiltration in two patients. The MICs for 90% of the most important pathogens were exceeded by the concentrations of the two drugs in plasma during the whole treatment of these patients.

Bayesian estimation of doxorubicin pharmacokinetic parameters

SummaryDoxorubicin was given by brief i.v. infusion (doses ranging from 25 to 72 mg/m2) to 28 patients for 2–7 successive courses of chemotherapy (68 courses studied in all). A Bayesian approach was developed to determine the individual pharmacokinetic parameters of doxorubicin. Statistical characteristics of the population pharmacokinetic parameters were first evaluated for 19 patients and a total of 30 courses, which, when combined with 4 individual plasma concentrations of drug, led to a Bayesian estimation of individual pharmacokinetic parameters for the remaining 38 courses. The estimated parameters for the elimination phase (A3/V1 andt1/2 elimination) and the residual plasma level at 48 h as computed by Bayesian estimation on this reduced sub-optimal sampling protocol were compared with a maximal likelihood estimation of these parameters. No statistically significant differences were found. Performance of the developed methodology was evaluated by computing bias and precision. The mean errors were −0.0315×10−4 l−1 for A3/V1, 0.0839 h fort1/2 elimination, and −0.22 ng/ml forc(48 h). The precision of the prediction of these three parameters (0.304×10−5 l−1, 3.34 h, and 0.659 ng/ml, respectively) remained lower than the interindividual standard deviation (1.42×10−4 l−1, 14.9 h, and 4.54 ng/ml, respectively). This procedure enables the estimation of individual pharmacokinetic parameters for doxorubicin at minimal cost and minimal disturbance of the patient.

Doxorubicin and doxorubicinol plasma concentrations and excretion in parotid saliva

SummaryThe pharmacokinetics of doxorubicin (DOX) and doxorubicinol (DOXol) was studied in six patients with various advanced neoplastic diseases who received 28–72 mg/m2 DOX (nine courses). Plasma and parotid saliva were collected over a 48-h period, and DOX and DOXol were quantified by high-performance liquid chromatography with fluorescence detection. As reported previously, a wide range of plasma levels were found among our patients. It appears that in addition to being quickly cleared from the plasma, both DOX and DOXol are excreted in detectable amounts in parotid saliva, a route of elimination that has been given little attention, if any. Excretion in the saliva exposes the mucosa of the upper gastroinfestinal tract to drug and may play a role in causing stomatitis in patients receiving DOX by the i.v. route. Since huge interindividual and pronounced intraindividual differences were found in S/P ratios that mostly were not systematically related to the plasma drug concentration, the concentration in parotid saliva was not useful in predicting the level of free DOX and DOXol in plasma. For the parent drug and its metabolite, the S/P ratios increased significantly with time during the 48-h period after dosing.