In vitro activity of expanded-spectrum pyridazinyl oxime ethers related to pirodavir: novel capsid-binding inhibitors with potent antipicornavirus activity.

Picornaviruses (PV) include human rhinovirus (HRV), the primary cause of the common cold, and the enteroviruses (EV), which cause serious diseases such as poliomyelitis, meningoencephalitis, and systemic neonatal disease. Although no compounds for PV infections have been approved in the United States, pirodavir was one of the most promising capsid-binding compounds to show efficacy in human clinical trials for chemoprophylaxis of the common cold. Susceptibility to hydrolysis precluded its use as an oral agent. We have developed orally bioavailable pyridazinyl oxime ethers that are as potent as pirodavir. Compounds BTA39 and BTA188 inhibited a total of 56 HRV laboratory strains and three clinical isolates as determined by neutral red uptake assay. At concentrations of <100 nM, BTA39 inhibited 69% of the HRV serotypes and isolates evaluated, BTA188 inhibited 75%, and pirodavir inhibited 59% of the serotypes and isolates. The 50% inhibitory concentrations (IC(50)s) for the two compounds ranged from 0.5 nM to 6,701 nM. The compounds also inhibited EV, including coxsackie A and B viruses (IC(50) = 773 to 3,608 nM) and echoviruses (IC(50) = 193 to 5,155 nM). BTA39 only inhibited poliovirus strain WM-1 at 204 nM, and BTA188 only inhibited poliovirus strain Chat at 82 nM. EV 71 was inhibited by BTA39 and BTA188, with IC(50)s of 1 and 82 nM, respectively. Both compounds were relatively nontoxic in actively growing cells (50% cytotoxic doses, >/=4,588 nM). These data suggest that these oxime ethers warrant further investigation as potential agents for treating selected PV infections.

Quinapril and its metabolite quinaprilat in human milk.

AIMS: To measure the milk to plasma ratio (M/P) of quinapril and its active metabolite quinaprilat in lactating mothers and to assess likely infant exposure. METHODS: A single dose of quinapril 20 mg was administered to six healthy mothers who had been breastfeeding their infants for at least 2 weeks. Blood was sampled for the measurement of quinapril and quinaprilat at 0, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16 and 24 h. Milk was collected for measurement of quinapril and quinaprilat concentrations over the periods -4-0, 0-4, 4-8, 8-12, 12-18, 18-24 h. The areas under the plasma and milk concentration-time curves were estimated and an M/P ratio derived for both quinapril and quinaprilat. RESULTS: The M/P ratio for quinapril was 0.12 (95% CI 0.09,0.14). No quinapril was detected in milk after 4 h. No quinaprilat was detected in any of the milk samples. The estimated 'dose' of quinapril that would be received by the infant was 1.6% (95% CI 1.0,2.2) of the maternal dose, adjusted for respective weights. CONCLUSIONS: Quinapril appears to be 'safe' during breastfeeding according to conventional criteria, although as always, the risk:benefit ratio should be considered when it is to be given to a nursing mother.

Gabapentin does not affect antipyrine clearance.

The effect of gabapentin on antipyrine clearance was assessed in 12 healthy male volunteers, using a known enzyme inducer, phenytoin, as control. Subjects received gabapentin 400 mg or phenytoin 100 mg three times daily for 2 weeks. Antipyrine tests were performed before, during, and after treatment with gabapentin or phenytoin. In contrast to phenytoin, chronic administration of gabapentin did not affect antipyrine clearance. Gabapentin appears to have little potential for drug interactions.

Inhibition of tacrine oral clearance by cimetidine.

Plasma tacrine, 1-hydroxytacrine, 2-hydroxytacrine, and 4-hydroxytacrine concentrations were measured in 12 healthy elderly subjects in this nonblinded two-period study to assess the effect of multiple doses of cimetidine on single-dose tacrine pharmacokinetics. Subjects received 40 mg tacrine (Cognex) alone and during multiple-dose cimetidine (300 mg four times a day) administration. Overall, tacrine and cimetidine were well tolerated by healthy elderly subjects. After coadministration of cimetidine with tacrine, plasma tacrine concentrations were approximately one-third higher than values after administration of tacrine alone; metabolite concentrations were also higher. Mean tacrine oral clearance was reduced by 30%; however, mean absorption rate and elimination half-life values were not affected by cimetidine. It was concluded that cimetidine inhibits first-pass hepatic extraction of tacrine by cytochrome P450 enzymes but has little effect on systemic drug clearance. Clinical considerations may dictate a reduction in tacrine dosage when tacrine is coadministered with cimetidine.

Lack of effect of tacrine administration on the anticoagulant activity of warfarin.

The effect of tacrine administration on prothrombin time was studied in 13 patients receiving prolonged warfarin therapy. After a 3-week baseline period and 5 days of placebo administration, patients received 20 mg tacrine four times daily for 5 days. Prothrombin times were determined during baseline, daily before the morning doses of placebo and tacrine, and 14 days after the last tacrine dose (closeout). Mean (+/- SD) prothrombin times were 16.2 +/- 2.8 seconds at baseline, 15.1 +/- 2.6 seconds during the placebo phase, 15.8 +/- 3.6 seconds during the tacrine phase, and 15.3 +/- 3.6 seconds at closeout, indicating that tacrine has no effect on the anticoagulant activity of warfarin. Alteration of warfarin dosage should not be required in patients receiving concurrent tacrine therapy.

Safety and tolerability of CI-979 in patients with Alzheimer's disease.

CI-979 ((E)-1,2,5,6-tetrahydro-1-methyl-3-pyridinecarboxaldehyde, O-methyloxime monohydrochloride), a novel muscarinic agonist, is being investigated as a potential treatment for Alzheimer's disease (AD). The objective of the present study was to determine the safety and tolerance of multiple, rising, oral doses of CI-979 in patients with AD. Ten male patients aged 59 to 74 years (mean 65 years) who met NINCDS criteria for AD were randomized to receive either CI-979 (eight patients) or placebo (two patients) according to a double-blind, parallel-group, rising-dose design. Doses were 0.5-mg q6h, 1-mg q12h, 1-mg q6h, 2-mg q12h, 2-mg q6h, 2.5-mg q6h, and 3-mg q6h. All doses were to be administered sequentially for 3 days each with the exception of the 2.5-mg q6h dose, which was to be administered for 1.5 days. Five patients receiving CI-979 discontinued study medication because of adverse events; two after receiving 2-mg q6h (10 doses), two after 2.5-mg q6h (5 doses), and one after 3-mg q6h (4 doses). The study was terminated following administration of the fourth 3-mg dose due to the nature and intensity of adverse events. Cholinergic symptoms including diaphoresis, hypersalivation, nausea, diarrhea, hypotension, chills, headache, flatulence, and urinary frequency and signs suggestive of parkinsonism (cogwheeling, tremor, pillrolling, posturing, and shuffling gait) were dose-limiting. The frequency and intensity of adverse events increased with increasing CI-979 dose. No other clinically significant CI-979-related changes occurred in physical examinations, clinical laboratory measurements, electrocardiograms, or ophthalmologic examinations. Steady-state trough plasma CI-979 concentrations increased in proportion to dose. In summary, CI-979 doses of 1-mg q6h were well tolerated by all patients; 2-mg q6h was tolerated by most patients, and 2.5-mg and 3-mg doses were poorly tolerated, Dose titration to a maximum of 2-mg q6h will therefore be used in initial efficacy trials of CI-979 in patients with AD.

Diuretic effects, pharmacokinetics, and safety of a new centrally acting kappa-opioid agonist (CI-977) in humans.

The diuretic effects, pharmacokinetics, and safety of CI-977, a new centrally acting selective kappa-opioid agonist, were determined in 16 healthy subjects. Subjects received single intramuscular doses of CI-977 (5, 15, or 25 micrograms) or placebo 1 week apart according to a randomized, double-blind, placebo-controlled, four-period, crossover design. Serial blood and urine specimens were collected after each dose. Significant dose-related decreases in negative free water clearance and urine osmolality and increases in urine volume were observed after administration of 15- and 25-micrograms doses of CI-977. CI-977 had no effect on urine electrolyte excretion or serum antidiuretic hormone. Absorption of CI-977 was rapid with individual tmax values ranging from 0.17 to 1.5 hours. Cmax and AUC(0-infinity) increased proportionally with dose. Individual elimination half-life values ranged from 0.6 to 3.3 hours and were independent of dose. Changes in free water clearance were related to CI-977 Cmax (r2 = 0.29, P = 0.0001) and AUC(0-4 hr) (r2 = 0.32, P = 0.0001) values. The most frequently reported adverse events after CI-977 administration were dizziness, fatigue, paresthesia, headache, vasodilatation (facial flushing), emotional lability, high feeling, and abnormal thinking. The frequency and intensity of adverse events increased with increasing CI-977 dose. In conclusion, CI-977 Cmax and AUC(0-infinity) increased in proportion to dose over the range of 5 to 25 micrograms; decreases in negative free water clearance were related to CI-977 dose and Cmax and AUC(0-4 hr) values; and the frequency and intensity of adverse events increased with increasing CI-977 dose.

Pharmacokinetics of gabapentin in subjects with various degrees of renal function.

The pharmacokinetics of oral gabapentin (400 mg) was studied in normal subjects and in subjects with various degrees of renal function. Sixty subjects participated in this three-center study. None of the subjects were receiving hemodialysis. Plasma and urine samples were collected for up to 264 hours after dosing, and concentrations of gabapentin were determined by high performance liquid chromatography. Apparent oral plasma clearance (CL/F) and renal clearance (CLR) of gabapentin decreased and maximum plasma concentration, time to reach maximum concentration, and half-life values increased as renal function diminished. Gabapentin CL/F and CLR were linearly correlated with creatinine clearance. Total urinary recovery of unchanged drug was comparable in all subjects, indicating that the extent of drug absorption was unaffected by renal function. There was no evidence of gabapentin metabolism even in subjects with severe renal impairment. In summary, impaired renal function results in higher plasma gabapentin concentrations, longer elimination half-lives, and reduced CL/F and CLR values. Based on pharmacokinetic considerations, it appears that the dosing regimen of gabapentin in subjects with renal impairment may be adjusted on the basis of creatinine clearance.

The pharmacokinetics of quinapril and quinaprilat in patients with congestive heart failure.

The pharmacokinetics of quinapril and its active metabolite quinaprilat were studied in 12 patients with congestive heart failure (CHF) after multiple oral doses of 10 mg quinapril twice daily. Six patients had an ejection fraction of < 35% and six had an ejection fraction between 35%-50%. Increases in the apparent elimination half-life and in AUC(0, 12h) values of quinaprilat were associated with smaller ejection fractions, decreased creatinine clearance, and increased patient age. Comparison with data from age-matched controls having comparable renal function suggests that creatinine clearance is the major determinant of quinaprilat clearance. CHF per se appears to have minimal effect. Dosing of quinapril in patients with CHF should be based on their renal function.

A phase I study of doxifluridine as a five-day stepped-dose continuous infusion.

Doxifluridine (5'-dFUR) is a prodrug of 5 fluorouracil (5-FU) synthesized in an attempt to improve the therapeutic index compared with 5-FU. In this phase I study, cohorts of three patients were treated by a 5-day continuous infusion with the dose increased daily, total doses ranging from 3.75 g/m2 to 20 g/m2/120 h. Twenty-nine patients received 54 courses (median 2, range 1-4). The dose-limiting toxicities were mucositis (Miller grade 3 in three patients and grade 4 in another) and grade 4 neutropenia and thrombocytopenia in two patients. Other toxicities included nausea, vomiting, and diarrhea, rash, and fever. Neurological toxicity was mild and no cardiovascular toxicity was recorded. Plasma and urine levels of 5'-dFUR and 5-FU were quantitated by high-performance liquid chromatography. Steady-state plasma levels between 167 ng/ml and 6,519 ng/ml were recorded and at these levels there was no evidence of saturation of doxifluridine metabolism. One patient at the maximum tolerated dose of 20 g/m2/120 h had a complete response in a nasopharyngeal carcinoma.

Pharmacokinetic study of doxifluridine given by 5-day stepped-dose infusion.

Doxifluridine (5'-deoxy-5-fluorouridine, 5'-dFUR) metabolism has been reported to be saturable and associated with a fall in clearance of the drug as the dose is increased. The aim of the present study was to determine the disposition of 5'-dFUR and 5-fluorouracil (5-FU) when 5'-dFUR was given as a 5-day infusion, with the infusion rate increased stepwise every 24 h. Measurement of plasma and urinary levels of 5'-dFUR and 5-FU at steady state for each infusion rate enabled the estimation of 5'-dFUR renal (ClR) and nonrenal (ClNR) clearance and 5-FU renal clearance. A total of 28 patients with histologically proven malignancy received 5-day courses of 5'-dFUR ranging in dose from 3.75 to 20 g/m2 per 120 h. The lowest dose given over 24 h was 0.25 g/m2, and the highest was 5 g/m2. Steady-state plasma levels of 5'-dFUR ranged from 167 to 6,519 ng/ml. At these plasma levels there was no evidence of significant saturation of 5'-dFUR metabolism; steady-state plasma levels of 5'-dFUR increased approximately linearly with dose, and nonrenal clearance did not change significantly with dose. There was also no evidence of nonlinearity in 5'-dFUR renal clearance. The mean (+/- SD) ClR of 5'-dFUR was 108.9 +/- 53.6 ml/min per m2 (range, 45.7-210 ml/min per m2), and the ClNR was 728 +/- 181 ml/min per m2 (range, 444-1,119 ml/min per m2). Renal clearance comprised 13% of the total 5'-dFUR clearance. The mean renal clearance of 5-FU was 100.8 +/- 48.6 ml/min per m2 (range, 23.5-198 ml/min per m2). There was considerable interpatient variability in 5'-dFUR renal and nonrenal clearance, even at the same dose level. We concluded that the administration of 5'-dFUR by the infusion method described avoided the saturation of nonrenal elimination processes reported to occur with shorter infusion schedules.

Two- versus 24-hour infusion of cisplatin: pharmacokinetic considerations.

The disposition of unchanged cisplatin was compared after two- and 24-hour intravenous (IV) infusion to eight patients with germ cell cancer (dose, 100 mg/m2), 14 patients with head and neck cancer (dose, seven patients 50 mg/m2; seven patients, 100 mg/m2). Patients were randomized to receive either a two- or 24-hour infusion in the first course of treatment and the reverse in the second course. Cisplatin renal clearance, total clearance, and the percentage of the dose excreted unchanged in urine were significantly lower with the longer infusion. Total clearance was 345 +/- 97.0 mL/min/m2 after the two-hour infusion and 268 +/- 70.7 mL/min/m2 after the 24-hour infusion (P less than .0001). Renal clearance was 79.1 +/- 35.3 mL/min/m2 and 34.1 +/- 14.9 mL/min/m2 (P less than .0001). The percentage of the dose excreted unchanged in urine was 22.9 +/- 6.5% and 12.8 +/- 4.0%, respectively (P less than .0001). The ratio of cisplatin renal clearance to creatinine clearance was 1.95 +/- .96 after the two-hour infusion and .90 +/- .40 after the 24-hour infusion (P less than .001). There was only a poor relationship between cisplatin renal clearance and creatinine clearance after a two-hour infusion (r2 = .05, P greater than .1) or 24-hour infusion (r2 = .18, P greater than .05). The severity of emesis was graded on a four-point scale and was significantly less with the 24-hour infusion than with the two-hour infusion (P less than .05). Twenty-four-hour infusion of cisplatin resulted in greater drug retention in patients due to reduced renal clearance, but was also associated with reduced emetic toxicity, probably as a result of lower peak plasma levels.

Influence of infusion time on unchanged cisplatin disposition in patients with ovarian cancer.

The disposition of unchanged cisplatin in ten patients with ovarian cancer receiving 2-h infusions of 100 mg/m2 was compared with that of ten patients receiving 6-h infusions. A high-performance liquid chromatographic assay specific for the unchanged drug was used and all collected samples were rapidly processed. Patients were catheterized for urine collections. Cisplatin renal clearance was significantly lower after 6-hour infusions (52.8 +/- 16.2 ml/min per m2) than after 2-h infusions (87.1 +/- 38.2 ml/min per m2) (P = 0.026). Total clearance was also lower and less variable, although not significantly, in patients receiving the longer infusion. No differences in nonrenal clearance, volume of distribution, or half-life were observed between the two groups. There was only a poor relationship between cisplatin renal clearance and creatinine clearance after 2-h (r2 = 0.02; P = 0.66) and 6-h infusions (r2 = 0.18; P = 0.23). A single cisplatin plasma level obtained at the end of the infusion proved to be a good predictor of total cisplatin clearance after both 2-h (r2 = 0.70; P = 0.0096) and 6-h infusions (r2 = 0.97; P = 0.0001). This level was not significantly related to the relatively small changes in creatinine clearance that occurred after three courses of treatment.

Alteration in doxorubicin and doxorubicinol plasma concentrations with repeated courses to patients.

Fifteen cancer patients were studied following repeated courses of doxorubicin (12-44 mg/m2) (together with other anticancer agents) to consider the possibility of enhanced metabolism as a cause of the previously reported reduction in doxorubicin plasma concentrations with repeated courses. Plasma doxorubicin and doxorubicinol concentrations were measured by a modified high-performance liquid chromatography/fluorescence method. The results presented confirmed the significant decline in doxorubicin plasma concentration-dose ratios measured 3 h after the 1-h infusion. Although the degree of this reduction varied markedly between patients, it was shown not to be associated with a rise in the plasma concentration-dose ratio of the major metabolite doxorubicinol or with altered renal and/or hepatic function, which may have influenced disposition. Alternative mechanisms that might explain the reduction in doxorubicin concentrations, such as increased doxorubicin clearance or volume of distribution, were not considered in the present study.

Renal clearance and protein binding of melphalan in patients with cancer.

The renal clearance of melphalan and the fraction unbound in plasma were determined after intravenous infusion of 5 mg/m2 over 5 min in nine patients with cancer to obtain information regarding the mechanism of renal handling of melphalan. Four of the patients underwent bone marrow transplantation and also received an IV dose of 220 mg/m2. Total melphalan clearance after the 5 mg/m2 dose ranged from 66.0 to 272 ml/min per m2; the percentage of the dose excreted unchanged in urine, from 2.5% to 92.8%; renal clearance, from 4.1 to 188 ml/min per m2; the fraction unbound in plasma, from 0.0598 to 0.460; and t1/2 beta, from 39.4 to 84.3 min. Unbound melphalan clearance and renal clearance calculated from the unbound fraction in plasma for each patient ranged from 441 to 3356 ml/min per m2 and 15 to 961 ml/min per m2 respectively and were not related to serum albumin, serum creatinine or creatinine clearance. The percentage of the dose excreted and melphalan renal clearance were not related to urine flow. There was evidence of active secretion of melphalan in the kidney an possible reabsorption. There were no significant paired differences in melphalan disposition between the high- and low-dose studies. Highly variable renal clearance involving active secretion may contribute in part to large interpatient differences in the total plasma clearance of melphalan in patients with cancer.

Disposition of unchanged cisplatin in patients with ovarian cancer.

The disposition of cisplatin (cis-diamminedichloroplatinum II) was studied in the first course of treatment in seven patients (56 +/- 12 years) with ovarian carcinoma by analytic methodology specific for the unchanged drug. Particular attention was paid to rapid blood and urine sample processing to avoid drug losses. Patients were catheterized for urine collections. During and after infusion, plasma levels of unbound cisplatin were simultaneously fitted to a one-compartment model. Creatinine clearance was determined at the same time as cisplatin renal clearance and was 38 +/- 16 ml/min/m2. Total clearance of unbound cisplatin was 253 +/- 48 ml/min/m2 and volume of distribution was 11.5 +/- 2.7 L/m2. Cisplatin half-life was similar when determined from plasma (31.6 +/- 6.0 minutes) or urinary excretion rate data (24.4 +/- 4.0 minutes). Urinary excretion of unchanged drug was 23.3% +/- 8.6% of the dose and renal clearance 56.9 +/- 18.0 ml/min/m2. Renal clearance exceeded creatinine clearance in all patients ratio = 1.9 +/- 1.2), confirming previous suggestions of active renal tubular secretion of cisplatin. Renal clearance was nonlinear with time in two of the patients who received the 2-hour infusion, possibly reflecting changing renal tubular reabsorption. Pharmacokinetic studies of unchanged cisplatin rather than total platinum are therefore practical and could be pursued in further studies defining cisplatin disposition in patients.

Pharmacokinetics of trimetrexate administered by five-day continuous infusion to patients with advanced cancer.

The disposition of the methotrexate analogue trimetrexate (TMTX, NSC 352122; 2,4-diammino-5-methyl-6-[(3,4,5-trimethoxyanilino)methyl]qui nazoline) was determined in a Phase I study in 16 patients with refractory or relapsing cancer. The drug was administered by continuous 5-day infusion at doses of 5 to 60 mg/m2/120 h (1-12 mg/m2 daily for 5 days). Plasma and urine collections were made during and after infusion and TMTX levels were quantitated by a specific and sensitive high-performance liquid chromatographic assay. Estimates of pharmacokinetic parameters were similar when determined by either compartmental or noncompartmental methods. There were no significant differences in parameters between the first and second courses of treatment to 10 of the patients. Significant linear relations between TMTX dose and the area under curve of plasma TMTX (r2 = 0.858, P = 0.0001) and the steady-state TMTX plasma level (r2 = 0.764, P = 0.0001) were established. Total TMTX clearance was 30.4 +/- 7.6 (SD) ml/min/m2, renal clearance 7.80 +/- 3.9 ml/min/m2, nonrenal clearance 23.2 +/- 7.1 ml/min/m2, volume of distribution 32.8 +/- 16.6 liters/m2, and terminal half-life 13.4 +/- 7.0 h. The percentage of the trimetrexate dose excreted unchanged in urine ranged from 8.4 to 40.7% (mean, 24.9 +/- 9.2%) and was related to creatinine clearance (r2 = 0.312, P = 0.010). Trimetrexate renal clearance was also related to urine flow (r2 = 0.330, P = 0.008). Trimetrexate pharmacokinetics was linear over the dose range 5 to 60 mg/m2 when given by 5-day continuous infusion to patients but there was evidence of urine flow-dependent renal clearance which requires further examination.

Creatinine clearance as a predictor of ultrafilterable platinum disposition in cancer patients treated with cisplatin: relationship between peak ultrafilterable platinum plasma levels and nephrotoxicity.

Ultrafilterable platinum (UP) disposition was studied in 22 cancer patients receiving their first course of cisplatin (50 to 140 mg/m2) by two-hour infusion. UP plasma and urinary platinum levels were quantitated using a high-performance liquid chromatographic (HPLC) assay, which was selective for cisplatin and active platinum metabolites. Creatinine clearance was determined in all patients at the time of the pharmacokinetic studies and ranged from 58 to 214 mL/min. Creatinine clearance was a poor predictor of UP disposition in patients, probably as a consequence of the complex renal clearance mechanism for UP in the human kidney, which involves both tubular secretion and reabsorption. However, the peak plasma level of UP was closely related to the area under curve (AUC) of UP (r2 = .831), P less than .0001) and was significantly correlated with the decline in creatinine clearance observed after four courses of cisplatin therapy to 12 of the patients (r2 = .727, P less than .005). Cisplatin dose and the AUC of UP were less satisfactory predictors of the change in creatinine clearance with four courses of therapy (r2 = .488, P less than .025 and r2 = .623, P less than .005). The large interpatient variability in all the parameters of cisplatin disposition measured in this study suggested that there may be a role for individualization of cisplatin dosage based on a peak level obtained in the first course of therapy. Longer term infusion of cisplatin could also be justified.

A model for ultrafilterable plasma platinum disposition in patients treated with cisplatin.

A model incorporating recent information regarding the specificity of a high-performance liquid chromatographic assay for "active" platinum in plasma ultrafiltrate, and the concept of mobile and fixed metabolites, was developed for cancer patients treated with cisplatin. Model parameters were determined using plasma and urinary platinum data obtained in 20 patients. It was assumed in the model that parent drug accounted for essentially all the platinum measured in plasma ultrafiltrate in the 2 h period immediately post infusion. At times greater than 4 h post infusion, platinum concentrations in plasma ultrafiltrate were assumed to be due entirely to reactive, mobile metabolites with possible cytotoxicity. The model accurately simulated platinum concentrations in plasma ultrafiltrate over a 24-h period following a 2-h infusion of 80 mg/m2 of cisplatin to seven patients, 100 mg/m2 to ten patients and 120 mg/m2 to three patients.

Pharmacokinetics of unchanged carboplatin (CBDCA) in patients with small cell lung carcinoma.

The disposition of the cisplatin analogue carboplatin was studied in seven patients with small cell lung cancer. Carboplatin 100 mg/m2 was administered without hydration by a 1-h infusion with VP16-213 120 mg/m2 on days 1, 2 and 3 of each course. Plasma and urine collections were made on days 1 and 3 of the first course of treatment. Carboplatin levels in plasma ultrafiltrate and urine were quantitated using a specific and sensitive, high-performance liquid chromatographic assay which involved sample clean-up on a Dowex-2 column prior to injection. Estimates of pharmacokinetic parameters determined using either compartmental or non-compartmental methods were comparable. There was no difference between carboplatin pharmacokinetic parameters determined on days 1 and 3 of treatment. The mean (+/- SD) carboplatin half-life determined from plasma data on day 1 was 105 +/- 30.4 min and was not significantly different from that determined using urinary excretion rate data (107 +/- 51.7 min). Urinary excretion rate plots showed that carboplatin elimination was mono-exponential for up to 14 h after infusion. Total-body clearance was 105 +/- 40.0 ml min-1 m-2, renal clearance 64.3 +/- 44.1 ml min-1 m-2, and volume of distribution 17.3 +/- 4.2 l/m2 on the 1st day of treatment. Of the administered dose, 58.4% +/- 21.2% was recovered in urine over a 24-h period after the start of the infusion. The mean renal clearance of carboplatin was comparable to creatinine clearance. Carboplatin disposition was clearly defined in the patients studied using analytical methodology specific for the unchanged drug.