Clinical pharmacokinetics of oxaliplatin: a critical review.

Oxaliplatin (cis-[(1R,2R)-1,2-cyclohexanediamine-N,N'] oxalato(2-)-O,O'] platinum; Eloxatine) is a novel platinum coordination complex used for the treatment of metastatic colorectal carcinoma in combination with fluoropyrimidines. The objective of this review is to integrate the key data from multiple studies into a single, comprehensive overview of oxaliplatin disposition in cancer patients. The pharmacokinetics (PKs) of unbound platinum in plasma ultrafiltrate after oxaliplatin administration was triphasic, characterized by a short initial distribution phase and a long terminal elimination phase (t1/2, 252-273 h). No accumulation was observed in plasma ultrafiltrate after 130 mg/m2 every 3 weeks or 85 mg/m2 every 2 weeks. Interpatient and intrapatient variability in platinum exposure (area under the curve(0-48)) is moderate to low (33 and 5% respectively). In the blood, platinum binds irreversibly to plasma proteins (predominantly serum albumin) and erythrocytes. Accumulation of platinum in blood cells is not considered to be clinically significant. Platinum is rapidly cleared from plasma by covalent binding to tissues and renal elimination. Urinary excretion (53.8 +/- 9.1%) was the predominant route of platinum elimination, with fecal excretion accounting for only 2.1 +/- 1.9% of the administered dose 5 days postadministration. Tissue binding and renal elimination contribute equally to the clearance of ultrafilterable platinum from plasma. Renal clearance of platinum significantly correlated with glomerular filtration rate, indicating that glomerular filtration is the principal mechanism of platinum elimination by the kidneys. Clearance of ultrafilterable platinum is lower in patients with moderate renal impairment; however, no marked increase in drug toxicity was reported. The effect of severe renal impairment on platinum clearance and toxicity is currently unknown. Covariates such as age, sex, and hepatic impairment had no significant effect on the clearance of ultrafilterable platinum, and dose adjustment due to these variables is not required. Oxaliplatin undergoes rapid and extensive nonenzymatic biotransformation and is not subjected to CYP450-mediated metabolism. Up to 17 platinum-containing products have been observed in plasma ultrafiltrate samples from patients. These include several proximate cytotoxic species, including the monochloro-, dichloro-, and diaquo-diaminocyclohexane platinum complexes, along with several other noncytotoxic products. Oxaliplatin does not inhibit CYP450 isoenzymes in vitro. Platinum was not displaced from plasma proteins by a variety of concomitant medications tested in vitro, and no marked PK interactions between oxaliplatin, 5-fluorouracil, and irinothecan have been observed. These results indicate that the additive/synergistic antitumor activity observed with these agents is not due to major alterations in drug exposure, and the enhanced efficacy is likely to be mechanistically based. Together, these PK, biotransformation, drug-drug interaction analyses and studies in special patient populations provide a firm scientific basis for the safe and effective use of oxaliplatin in the clinic. These analyses also reveal that the pharmacological activity of oxaliplatin may be attributable, at least in part, to the unique pattern of platinum disposition observed in patients.

Phase I pharmacokinetic study of the novel antitumor agent SR233377.

SR233377 is a novel thioxanthenone analogue that demonstrated solid tumor selectivity in vitro with activity confirmed in vivo against several murine tumors including those of colon, pancreas, and mammary origin. Its primary preclinical dose-limiting toxicities included myelosuppression and neurological toxicity. The neurological toxicity was acute and could be ameliorated in mice when the drug was administered as a 1-h infusion instead of rapid i.v. injection. As a result of its preclinical efficacy profile, SR233377 entered Phase I clinical investigation. The compound was administered i.v. over 2 h on day 1 repeated every 28 days. The starting dose was 33 mg/m2 (one-tenth the mouse LD10). Escalations continued to 445 mg/m2 (six escalations), where dose-limiting toxicity was observed. At this dose, acute ventricular arrhythmias, including one patient with torsades de pointes and transient cardiac arrest, occurred. Because this toxicity might have been related to the plasma peak, the protocol was amended to a 24-h infusion beginning at 225 mg/m2. With this dose, prolongation of the corrected QT interval (QTc) over the pretreatment levels resulted. Because prolonged QTc is a known forerunner to acute ventricular arrhythmias, clinical development of SR233377 was stopped. However, preclinical antitumor and toxicity studies with analogues are underway with hopes of identifying a new clinical candidate with similar antitumor effects that is devoid of cardiac toxic effects.

In-vivo phenotyping for CYP3A by a single-point determination of midazolam plasma concentration.

We investigated whether a single plasma midazolam concentration could serve as an accurate predictor of total midazolam clearance, an established in-vivo probe measure of cytochrome P450 3A (CYP3A) activity. In a retrospective analysis of data from 224 healthy volunteers, non-compartmental pharmacokinetic parameters were estimated from plasma concentration-time curves following intravenous (IV) and/or oral administration. Based on statistical moment theory, the concentration at the mean residence time (MRT) should be the best predictor of the total area under the curve (AUC). Following IV or oral midazolam administration, the average MRT was found to be approximately 3.5 h, suggesting that the optimal single sampling time to predict AUC was between 3 and 4 h. Since a 4-h data point was common to all studies incorporated into this analysis, we selected this time point for further investigation. The concentrations of midazolam measured 4 h after an IV or oral dose explained 80 and 91% of the constitutive interindividual variability in midazolam AUC, respectively. The 4-h midazolam measurement was also an excellent predictor of drug-drug interactions involving CYP3A induction and inhibition. Compared with baseline values, the direction and magnitude of change in midazolam AUC and the 4-h concentration were completely concordant for all study subjects. We conclude that a single 4-h midazolam concentration following IV or oral administration represents an accurate marker of CYP3A phenotype under constitutive and modified states. Moreover, the single-point approach offers an efficient means to phenotype and identify individuals with important genetic polymorphisms that affect CYP3A activity.

Determination of myocardial and serum digoxin concentrations in children by specific and nonspecific assay methods.

After obtaining samples at open heart surgery, serum and right atrial digoxin concentrations were measured in 25 children by a nonspecific, direct radioimmunoassay method (NS) and by a specific method in which digoxin was separated from its metabolites by HPLC before radioimmunoassay was applied to the digoxin fraction (S). Digoxin was detectable by S assay (sensitivity 0.1 ng/g) in 16 heart specimens and 22 serum samples. The mean and range of the S/NS ratio was 0.74 (0.23 to 2.63) for serum and 0.81 (0.068 to 1.38) for atrial tissue. By NS assay the mean and range of the atrial/serum ratio was 78.1 (2.4 to 340, n = 21) and by S assay the corresponding values were 100 (10.7 to 318, n = 15). A multiple linear regression indicated that 72.5% of the variance of the heart digoxin concentrations measured by S assay were accounted for by the variables height, body weight, daily digoxin dose before operation, plasma digoxin concentration by S assay, and BUN.

Pharmacokinetics of ibuprofen in man. I. Free and total area/dose relationships.

Ibuprofen kinetics were studied in 15 subjects after four oral doses. Plasma levels of both total and free ibuprofen were measured for 12 hr, and urine was collected for 48 hr after the doses. All subjects showed a nonlinear relationship between dose and total ibuprofen plasma AUC. Free ibuprofen plasma AUC, however, was linearly related to the dose, suggesting that oral clearance based on free drug was dose independent. Urinary recovery data indicated that efficiency of absorption was dose independent.

Effects of age on the clinical pharmacokinetics of ibuprofen.

The pharmacokinetics of ibuprofen (Motrin) were studied in 17 normal elderly men and women aged 65 to 78 years. Total and free unbound plasma concentrations of ibuprofen were determined 12 hours after single oral doses of 400, 800, and 1,200 mg. These results were then compared with those of a similar study involving 15 normal young men 22 to 35 years old. The two age groups showed no statistically significant differences in any pharmacokinetic parameter studied. Therefore, according to this study, advanced age has only minimal influence on the pharmacokinetics of ibuprofen, and dosage apparently does not need to be adjusted for age.

In vitro drug metabolism and pharmacokinetics of diazepam in cynomolgus monkey hepatocytes during culture for six days.

Diazepam (DZ), N-desmethyl diazepam (NOR) and temazepam (TEM) were used as substrates in drug metabolism studies to characterize the changes in cytochrome P-450 mono-oxygenase pathways in hepatocytes isolated from cynomolgus monkeys, during culture for 6 days. Hepatocytes were incubated with DZ (20 microM), NOR (6 microM) or TEM (20 microM) for 3 hr at 3, 24, 48, 96 and 144 hr post-isolation in culture, and the profiles of disappearance of DZ, as substrate, and appearance of its metabolites determined. Major metabolites were NOR, TEM and oxazepam (OX). The kinetic profiles for the disappearance of DZ and the accumulation of metabolite were analysed using a four-compartment model and constants for the rates of formation of the metabolites were derived. There were significant changes during the period in culture for the rate constants of DZ demethylation, but no alteration in the 3-hydroxylation activities. Rates of DZ metabolism were unchanged during the initial 2 days in culture and well maintained for the subsequent 4 days, despite a fall in total cytochrome P-450 to 23% of initial values after 6 days. Cynomolgus monkey hepatocytes produce similar metabolite profiles for DZ to those found in man, both in vitro and in vivo, indicating that cynomolgus monkey hepatocytes may represent a relatively stable and valuable model of human drug metabolism.

Accumulation and time to steady state for drugs subject to enterohepatic cycling: a stimulation study.

A physiologically realistic model was used to investigate through simulation the multiple-dose behavior of drugs subject to enterohepatic cycling. The model included separate liver and gallbladder compartments and instantaneous emptying of the gallbladder at regular intervals of length phi. Two half-lives are described, only one of which is predictive of time to steady state and accumulation. This predictive half-life would be obtained if plasma samples were taken at regular intervals equal to phi, and has been termed the effective half-life. Incorporation of gallbladder emptying at irregular intervals into the model did not materially alter our conclusions regarding the existence and predictive nature of the effective half-life.

Influence of phenobarbitone pretreatment on disposition of amidopyrine and its metabolites in rat.

Plasma concentration-time profiles for amidopyrine and its primary desmethyl metabolite have been determined in control rats and in rats pretreated with phenobarbitone. The kinetics of both compounds indicate enhanced clearance following pretreatment. Metabolite excretion in urine, bile and breath support the plasma data. It would appear that pheno barbitone pretreatment results in quantitative but not qualitative changes in the metabolism of amidopyrine in rat.

Dose regimen adjustment for milrinone in congestive heart failure patients with moderate and severe renal failure.

This study was designed to test a proposed dose modification for intravenous milrinone in congestive heart failure patients (CHF, NYHA I-II) with either moderate or severe renal impairment. All the patients were administered an intravenous loading dose of drug at 50 micrograms kg-1 over 10 min. This was followed by an 18 h maintenance infusion of milrinone at 0.45 or 0.35 micrograms kg-1 min-1 for the moderate (chromium-EDTA clearance of 31-75 mL min-1, n = 10) and severe renally impaired subjects (chromium-EDTA of clearance 10-30 mL min-1, n = 11), respectively. Plasma and urine samples were collected for up to 34 h and analysed for parent drug by validated HPLC methods. The mean (+/- s.d.) steady-state plasma concentrations of milrinone were within the therapeutic range (100-300 ng mL-1) for both groups, with values of 239 +/- 71 ng mL-1 and 269 +/- 32 ng mL-1 for the moderate and severe patients, respectively. No statistical differences were observed between the steady-state values for the two groups. With the exception of two patients per group, individual steady-state levels were also within the therapeutic range. Those outside the nominal range showed steady-state levels, ranging between 308 and 353 ng mL-1, that were not associated with any serious adverse events.(ABSTRACT TRUNCATED AT 250 WORDS)

The antipyrine breath test in the rat: a pharmacokinetic model.

Breath tests have been widely advocated for use as non-invasive probes of mixed function oxidase activity in vivo. A catenary sequence of events begins with demethylation and results in the exhalation of 14CO2. Intermediates in this chain include formaldehyde and formate. In this current study [14C]-antipyrine, [14C]-formaldehyde and [14C]-formate have been administered to rats. The data from these one carbon intermediates lead to the conclusion that demethylation is not the rate-limiting step in the antipyrine breath test in the rat. The resultant 14CO2 exhalation rate time profiles have been used to derive a compartmental pharmacokinetic model for the antipyrine breath test in the rat. The simplest catenary model (Antipyrine----formaldehyde----formate----CO2) did not adequately describe the observed data. A compartment in equilibrium with the central compartment for formate was needed to characterize fully the observed data. The derived compartmental model was able to predict qualitatively the effects of phenobarbitone induction on the antipyrine breath test. The quantitative agreement between the model prediction and the observed data could be improved by incorporating the changes in one carbon metabolism produced by phenobarbitone.

Characterization of the highly variable bioavailability of tiludronate in normal volunteers using population pharmacokinetic methodologies.

Currently, the use of classical bioequivalence criteria is being called into question for certain classes of drugs such as bisphosphonates. These compounds typically possess a wide therapeutic index but may be characterized by low and variable absorption. The purpose of this communication was to characterize the highly variable bioavailability of tiludronate using a population pharmacokinetic method (NONMEM program) and compare the results to a standard 2 way cross-over bioequivalence trial in healthy subjects. Over 3500 plasma samples from 153 healthy subjects, representing 12 different clinical trials were pooled for mixed effect modeling purposes (complete data set). These studies, conducted under single and multiple dose conditions, contained all the directly comparable data available in healthy subjects administered a 400 mg dose of tiludronate. A two compartment model with first order absorption was fit to the plasma concentration-time data and a term for relative bioavailability (BA) was included. Intersubject and residual variability were modeled using a constant coefficient of variation (CCV) model. A pilot model development data set was obtained from a 24 subject cross-over bioequivalence study. Population estimates of BA and its associated 90% confidence interval of 1.12 and 0.89-1.35 compared favorably to standard bioequivalence methodology (1.15 and 0.93-1.42, respectively). Since a good fit of predicted and observed plasma concentrations as well as estimates of BA were obtained, a two compartment model with a term for BA was then applied to the complete data set. Under these conditions, BA and its 90% confidence interval were found to be 1.17 and 0.98-1.36. Intersubject variability of 31%, compared with 38% in the pilot model development data set and residual variability of 38% were seen. No differences in absorption characteristics as measured by Ka were found. Good agreement between the population pharmacokinetic parameters were observed when the pilot data set was compared with the full data set. The proposed model was confirmed by creating 10 additional smaller data sets that were matched for the number of subjects given both formulations under single and multiple dose conditions. No change in the estimate of BA was observed under these study conditions. This study demonstrated that population pharmacokinetic methodology can be applied successfully to problematical bioequivalence issues that may occur during the development process. Increasing the number of subjects in the overall analysis did not alter the estimate of BA or its 90% confidence interval, when compared to the original cross-over bioequivalence study. Bayesian approaches can be of value in large clinical trials where typically relatively few plasma samples are obtained from individual subjects.

High-performance liquid chromatographic determination of ibuprofen and its major metabolites in biological fluids.

A sensitive and selective high-performance liquid-chromatographic assay for ibuprofen and its major metabolites in biological fluids is described. To ensure good chromatographic separation the drug and metabolites were run on a gradient elution system and detected with a variable wavelength detector set at 220 nm. A second, more rapid, isocratic system is also described for the detection of only ibuprofen.

Aminopyrine demethylation kinetics. Use of metabolite exhalation rates as an index of enhanced mixed-function oxidase activity in vivo.

The usefulness of determining aminopyrine demethylation kinetics via monitoring of metabolite exhalation rats had been assessed. In rats receiving [N-dimethyl-14C]aminopyrine, a biexponential decline in the 14CO2 exhalation rate is apparent when monitoring is continued over a 5 to 6-hr period. Both the fast phase (representing the first demethylation) and the slower phase (representing the second demethylation) are markedly influenced by phenobarbital and promethazine pretreatment. These changes are consistent with enhanced mixed-function oxidase activity. Examination of the urinary excretion products of aminopyrine obtained in these studies support this claim. The sensitivity of the above index of mixed-function oxidase activity is increased considerably by the use of crossover experimental designs. Considerable interanimal variation is observed in the metabolite production in both exhaled air and urine from rats administered aminopyrine.