Phillip A. Reece

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.

Effect of body weight on the pharmacokinetics of cyclophosphamide in breast cancer patients

SummaryCyclophosphamide pharmacolinetics have been studied in 16 female patients with advanced breast cancer. The group included 7 patients who were >20%, ≤30% over ideal body weight and 5 patients who were >30% over ideal body weight. Cyclophosphamide plasma elimination half-lives ranged between 152 and 984 min (mean 457 min), the apparent volume of distribution between 19.1 and 62.31 (mean 36.11), and plasma clearance between 25.9 and 166.6 ml/min (mean 69.5 ml/min). There was a significant positive correlation (r=0.624,P=0.010) between body weight and plasma elimination half-life, and a significant negative correlation between body weight and cyclophosphamide clearance when normalized to body surface area (r=0.578,P=0.019) or normalized to ideal body weight (r=0.531,P=0.0345). the apparent volume of distribution did not correlate with body weight. The results show that cyclophosphamide disposition is altered in patients with increased body weight.

Effect of CI-988 on cholecystokinin tetrapeptide-induced panic symptoms in healthy volunteers

A randomized, placebo-controlled, double-blind, three-way crossover design was used to evaluate the effectiveness of single oral 100 mg doses of CI-988, a cholecystokinin B (CCKB) antagonist, in attenuating panic symptoms induced by intravenous injection of cholecystokinin-tetrapeptide (CCK-4). Thirty healthy men received the following treatments on three separate occasions: placebo capsules/placebo, placebo capsules/CCK-4, or CI-988 capsules/CCK-4. There was no marked difference in the number, time to onset, or duration of panic symptoms between CI-988/CCK-4 and placebo/CCK-4. There was, however, a 14% difference in sum intensity scores between these treatments that was statistically significant (p = 0.039). The symptoms most affected by CI-988 were cold chills/hot flushes, chest pain/discomfort, and anxiety/fear/apprehension. Panic attack frequency also decreased following CI-988 treatment (8/30 vs. 16/30; p = 0.035). This decrease, amid otherwise modest effects, could be explained by a preferential effect of CI-988 on the subjective experience of anxiety/fear/apprehension. Possible reasons for the relatively modest effects of CI-988 on CCK-4-induced panic symptoms are discussed.

The effect of food on oral melphalan absorption.

SummaryFifteen patients receiving oral melphalan (4.2–5.3 mg/m2) for a variety of neoplastic disorders were studied. Ten patients received the drug on separate occasions, with and without a standardized breakfast. Eight of these patients also received an IV bolus dose (5 mg/m2) to determine bioavailability. Serial melphalan plasma samples were taken over 5 h after administration and assayed by high-performance liquid chromatography. The median area under the curve (AUC) when taken fasting was 179 (range 95–336) ng · h · ml-1, and when taken with food, 122 (47–227) ng · h · ml-1, the median reduction being 39% (P0.01). In one patient, who died before completing the study, the drug was not detectable at all after being taken with food. In the eight patients who were also given IV melphalan, the median terminal melphalan half-life (57 min, range 38–71) was no different from its oral half-life [55 (27–104) min fasting; 55 (30–72) min with food] (P>0.1). In these patients bioavailability was 85% (26–96)% when the drug was taken fasting and 58% (7–99)% when taken with food (P0.025). Median clearance following IV administration was 362 ml/min/m2 (range 104–694). It was found that the melphalan level in a single plasma sample drawn 1.5 h after administration was highly predictive of oral melphalan AUC (rs=0.915, P0.1). This study suggests that to ensure optimum absorption of the drug, melphalan should not be taken with food.

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.

Renal clearance and protein binding of melphalan in patients with cancer

SummaryThe 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 t1/2β, 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 exctreted 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.

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

SummaryThe 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.

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

SummaryThe 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, highperformance 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 pharmacolinetic 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. Totalbody 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.

Nonlinear renal clearance of ultrafilterable platinum in patients treated with cis-dichlorodiammineplatinum (II).

SummaryNonlinear renal clearance of ultrafilterable platinum was observed in 5 of 7 patients given cis-dichlorodiammineplatinum (II) in doses of 50–140 mg/m2 by short-term infusion (2h). Average renal clearance determined during and 24 h after infusion ranged from 100 to 543 ml/min and always exceeded creatinine clearance, suggesting that ultrafilterable platinum was renally secreted. Saturable tubular reabsorption was postulated on the basis that renal clearance was highest at peak plasma and urinary levels and fell as the levels declined. Although an overall relationship between dose and renal clearance was not apparent, one patient receiving the highest dose (140 mg/m2) had elevated average renal clearance (485 ml/min), probably associated with saturation of reabsorption, whereas a patient receiving 50 mg/m2 had the lowest average renal clearance (100 ml/min), indicating that either active secretion was lower, or tubular reabsorption was saturated. One patient also showed urine-flow-dependent changes in renal clearance. Four patients had transient rises in ultrafilterable platinum levels, which were attributed to changes in renal tubular reabsorption. The results suggest that renal clearance of ultrafilterable platinum is probably dependent on cis-DDP dose, urine flow rate, and individual variability in the extent of active secretion and tubular reabsorption. A sensitive HPLC method was applied and ultrafilterable platinum was detected in the plasma of all patients 24 h after infusion. Renal tubular reabsorption may result in prolonged plasma levels of ultrafilterable platinum, which could contribute to the drugs antitumour effect.

Effect of L-leucine on oral melphalan kinetics in patients

SummaryMelphalan uptake in the intestine has recently been shown to be an energy-dependent process which is affected by metabolic inhibitors. It is therefore theoretically possible that amino acids in food could reduce melphalan absorption by competing for uptake at the sites of absorption in the intestine. Since L-leucine has been shown to be the most potent inhibitor of melphalan transport into cells in vitro, this amino acid was chosen for the present study in patients. Oral melphalan (4.5±0.5 mg/m2) was given to ten fasting patients with and without a 2-g oral dose of L-leucine on separate randomized occasions at least 1 week apart. Melphalan plasma levels were measured by high-performance liquid chromatography (HPLC) for 5-h after dosing. L-Leucine plasma levels were measured by HPLC before and at 1 h after dosing. The area under the curve for melphalan was lower in seven of the patients after L-leucine. Plasma L-leucine levels 1 h after melphalan administration were 15.4±3.7 μg/ml fasting and 35.4±5.2 μg/ml after L-leucine. The results indicate that L-leucine can reduce plasma melphalan levels in some patients, probably through a reduction in absorption of the drug from the gastrointestinal tract. However, the effect, like that of food, is highly variable.