Effects of rifampin and mefenamic acid on the pharmacokinetics and pharmacodynamics of dapagliflozin.

AIMS: Dapagliflozin is a selective sodium glucose cotransporter 2 (SGLT2) inhibitor that decreases serum glucose by reducing renal glucose reabsorption, thereby promoting urinary glucose excretion. Dapagliflozin is primarily metabolized via the uridine diphosphate-glucuronosyltransferase (UGT)1A9 pathway to its major inactive metabolite, dapagliflozin 3-O-glucuronide. The aim of this study was to evaluate the potential for drug-drug interaction between dapagliflozin and two potential UGT1A9 modulators. METHODS: The results of two open-label, non-randomized, single-sequence studies are reported in which the effects of rifampin (a pleiotropic drug-metabolizing enzyme inducer; study 1) and mefenamic acid (a strong UGT1A9 inhibitor; study 2) were evaluated on the pharmacokinetics and pharmacodynamics (assessed by urinary glucose excretion [UGE]) of dapagliflozin in healthy subjects. In study 1, 14 subjects received single doses of dapagliflozin 10 mg alone and in the presence of rifampin 600 mg QD (6 days). In study 2, 16 subjects received single doses of dapagliflozin 10 mg alone and in the presence of mefenamic acid 250 mg q6h (5 days). RESULTS: Rifampin reduced total exposure (area under the concentration-time curve from time 0 to infinity [AUC0-inf]) to dapagliflozin by 22% and mefenamic acid increased dapagliflozin AUC0-inf by 51%. No clinically meaningful effect of rifampin or mefenamic acid on the pharmacokinetics of dapagliflozin or on dapagliflozin-mediated urinary glucose excretion was observed. CONCLUSION: Modest changes in dapagliflozin exposure were seen with rifampin and mefenamic acid with minor changes in UGE, none of which were considered clinically meaningful.

Effect of saxagliptin on the pharmacokinetics of the active components of Ortho-Cyclen(®), a combined oral contraceptive containing ethinyl estradiol and norgestimate, in healthy women.

Saxagliptin (Onglyza™) is a dipeptidyl peptidase-4 (DPP4) inhibitor for treating type 2 diabetes mellitus. This open-label, randomized, two-way crossover study in 20 healthy female subjects investigated the effect of saxagliptin on the pharmacokinetics (PK) of the active components of a combined oral contraceptive (COC). Subjects received either COC (Ortho-Cyclen(®)) once daily (QD) for 21 days, then 5 mg saxagliptin QD + COC QD for 21 days, or vice versa. Coadministration of saxagliptin and COC did not alter the steady-state PK of the primary active oestrogen (ethinyl estradiol) or progestin (norelgestromin) COC components. The area under the concentration-time curve (AUC) and peak plasma concentration (Cmax) of an active metabolite of norelgestromin (norgestrel) were increased by 13 and 17%, respectively, a magnitude that was not considered clinically meaningful. Coadministration of saxagliptin and COC in this study was generally well-tolerated. Saxagliptin can be co-prescribed with an oestrogen/progestin combination for women taking oral contraceptive.

Effect of a high-fat meal on the pharmacokinetics of dapagliflozin, a selective SGLT2 inhibitor, in healthy subjects.

Dapagliflozin is a potent and selective inhibitor of sodium-glucose co-transporter type 2 that is being developed for the treatment of type 2 diabetes mellitus. This open-label, randomized, two-period, two-treatment (single doses of 10-mg dapagliflozin fasted or fed), crossover study was conducted to evaluate the effect of a high-fat meal on the pharmacokinetics of dapagliflozin in 14 healthy subjects. Compared to the fasted state, a high-fat meal decreased mean dapagliflozin maximum plasma concentrations (C(max) ) by 31%, increased the time to C(max) (T(max) ) by 1 h, but did not affect overall dapagliflozin systemic exposure [area under the plasma concentration-time curve (AUC)]. As the cumulative (daily) amount of glucose excreted in the urine induced by dapagliflozin is dependent upon dapagliflozin AUC, the effect of food on dapagliflozin C(max) is unlikely to have a clinically meaningful effect on dapagliflozin's efficacy. On the basis of these findings, dapagliflozin can be administered without regard to meals.

Pharmacokinetics and pharmacodynamics of dapagliflozin, a novel selective inhibitor of sodium-glucose co-transporter type 2, in Japanese subjects without and with type 2 diabetes mellitus.

AIMS: Dapagliflozin, a selective, orally active inhibitor of the renal sodium-glucose co-transporter type 2 (SGLT2) is in development for the treatment of type 2 diabetes mellitus (T2DM). Here, the pharmacokinetics (PK) and pharmacodynamics (PD) of dapagliflozin were evaluated in healthy Japanese subjects and in Japanese subjects with T2DM. METHODS: Two studies were conducted: a single-ascending dose (SAD) study (2.5-50 mg) in 32 healthy subjects and a multiple-ascending dose (MAD) study (2.5-20 mg QD for 14 days) in 36 subjects with T2DM. Safety and tolerability were assessed in both studies. Single and multiple dose PK of dapagliflozin and its inactive major metabolite, dapagliflozin 3-O-glucuronide, and PD (urinary glucose parameters) were characterized. Plasma glucose parameters were assessed over 14 days in the MAD study. RESULTS: No serious adverse events or discontinuations due to adverse events occurred in either study. In healthy and T2DM subjects, dapagliflozin was rapidly absorbed with a time to maximum plasma concentration of 0.5-1.3 h. Systemic exposure of dapagliflozin and dapagliflozin 3-O-glucuronide, measured by maximum plasma concentration and area under the plasma concentration-time curve, increased proportional to dose. On a molar basis, systemic exposure to dapagliflozin 3-O-glucuronide was similar to parent dapagliflozin. There was a dose-related increase in the amount of glucose excreted in the urine (SAD and MAD), which was associated with dose-related decreases in plasma glucose parameters in subjects with T2DM (MAD). CONCLUSIONS: Dapagliflozin was well tolerated and showed predictable dose-proportional PK and PD parameters in both healthy and T2DM Japanese subjects.

Differential effects of omeprazole and pantoprazole on the pharmacodynamics and pharmacokinetics of clopidogrel in healthy subjects: randomized, placebo-controlled, crossover comparison studies.

Four randomized, placebo-controlled, crossover studies were conducted among 282 healthy subjects to investigate whether an interaction exists between clopidogrel (300-mg loading dose/75-mg/day maintenance dose) and the proton-pump inhibitor (PPI) omeprazole (80 mg) when they are administered simultaneously (study 1); whether the interaction, if any, can be mitigated by administering clopidogrel and omeprazole 12 h apart (study 2) or by increasing clopidogrel to 600-mg loading/150-mg/day maintenance dosing (study 3); and whether the interaction applies equally to the PPI pantoprazole (80 mg) (study 4). Relative to levels after administration of clopidogrel alone in studies 1,2,3, and 4, coadministration of PPI decreased the AUC(0-24) of the clopidogrel active metabolite H4 by 40, 47, 41, and 14% (P ≤ 0.002), respectively; increased maximal platelet aggregation (MPA) induced by 5 micromol/l adenosine diphosphate (ADP) by 8.0, 5.6, 8.1, and 4.3% (P ≤ 0.014), respectively; and increased the vasodilator-stimulated phosphoprotein phosphorylation-platelet reactivity index (VASP-PRI) by 20.7, 27.1, 19.0 (P < 0.0001), and 3.9% (P = 0.3319), respectively. The results suggest that a metabolic drug-drug interaction exists between clopidogrel and omeprazole but not between clopidogrel and pantoprazole.

Lack of pharmacokinetic interaction between dapagliflozin, a novel sodium-glucose transporter 2 inhibitor, and metformin, pioglitazone, glimepiride or sitagliptin in healthy subjects.

AIMS: Dapagliflozin increases urinary glucose excretion by selectively inhibiting renal sodium-glucose transporter 2, an insulin-independent mechanism of action that may be complementary to that of other oral antidiabetes drugs. The current studies assessed the potential for pharmacokinetic (PK) interaction between dapagliflozin and pioglitazone, metformin, glimepiride or sitagliptin in healthy subjects following single-dose administration. METHODS: In open-label, randomized, three-period, three-treatment crossover studies, 24 subjects received 50 mg dapagliflozin, 45 mg pioglitazone or the combination, while 18 subjects received 20 mg dapagliflozin, 1000 mg metformin or the combination. In an open-label, randomized, five-period, five-treatment, unbalanced crossover study, 18 subjects first received 20 mg dapagliflozin, 4 mg glimepiride or the combination, and afterward 100 mg sitagliptin or sitagliptin plus 20 mg dapagliflozin. Blood samples were taken over 72 h of each treatment period. Lack of PK interaction was defined as the ratio of geometric means and 90% confidence interval (CI) for combination:monotherapy being within the range of 0.80-1.25. RESULTS: Co-administration of dapagliflozin with pioglitazone, metformin, glimepiride or sitagliptin had no effect on dapagliflozin maximum plasma concentration (C(max) ) or area under the plasma concentration-time curve (AUC). Similarly, dapagliflozin did not affect the C(max) or AUC for the co-administered drug, except for slight extensions of the 90% CI for the ratio of geometric means for glimepiride AUC (upper limit 1.29) and pioglitazone C(max) (lower limit 0.75). All monotherapies and combination therapies were well tolerated. CONCLUSION: Dapagliflozin can be co-administered with pioglitazone, metformin, glimepiride or sitagliptin without dose adjustment of either drug.

A dose-escalation study of the safety, tolerability, and pharmacokinetics of intravenous gatifloxacin in healthy adult men.

STUDY OBJECTIVES: To examine single- and multiple-dose safety, tolerability, and pharmacokinetics of gatifloxacin administered as daily 1-hour intravenous infusions for 14 days, and to determine the effect of gatifloxacin on glucose tolerance, pancreatic beta-cell function, and electrocardiogram (ECG). DESIGN: Randomized, double-blind, placebo-controlled, ascending-dose study. SETTING: Bristol-Myers Squibb, Clinical Pharmacology Unit, Princeton, New Jersey, USA. PATIENTS: Forty healthy male subjects, eight in each of five groups, were enrolled to receive sequential doses of gatifloxacin: 200 mg (10 mg/ml), 200 mg (1 mg/ml), and 400, 600, and 800 mg (2 mg/ml); six subjects per group received active drug and two received placebo. INTERVENTIONS: A single dose of the drug was administered as an intravenous infusion over 1 hour. After a 72-hour washout period, the drug was administered once/day for 14 days by 1-hour intravenous infusion. Physical examinations, ECGs, spirometry, and clinical laboratory tests, including glucose tolerance test (GTT) and assessment of glucose homeostasis, were performed before treatment and on selected dosing days. A safety evaluation was performed before escalating doses. No intrasubject dose escalation was permitted. MEASUREMENTS AND MAIN RESULTS: The pharmacokinetics of gatifloxacin were dose linear and time independent after intravenous administration over the range of 200-800 mg. After daily repeated administration, a predictable, modest accumulation was observed; steady state was reached by the third dose. Approximately 80% of the dose was recovered as unchanged drug in urine. Mean changes (before the first dose to the last dose) after oral GTT and in fasting serum glucose, insulin, and C-peptide concentrations were comparable among the gatifloxacin and placebo treatment groups. A mild, transient decrease in serum glucose was associated with the end of the 1-hour infusion of gatifloxacin. No clinically important changes in QTc interval or spirometry occurred. The most frequent treatment-related adverse effects were local intravenous site reactions, which were associated with dose and/or concentration of intravenous solution. CONCLUSION: Gatifloxacin was safe and well tolerated at intravenous doses of up to 800 mg/day for 14 days. Gatifloxacin pharmacokinetics were linear and time independent.

Interchangeability of 400-mg intravenous and oral gatifloxacin in healthy adults.

STUDY OBJECTIVE: To evaluate the interchangeability of 400-mg intravenous and oral doses of gatifloxacin. DESIGN: Randomized, open-label, crossover study. SETTING: GFI Pharmaceutical Services, Inc., Evansville, Indiana, USA. SUBJECTS: Twenty-four healthy men and women (12 of each gender), aged 18-42 years. INTERVENTIONS: Subjects received single doses of gatifloxacin 400 mg either by intravenous infusion over 1 hour or a 400-mg tablet orally with 240 ml of water, each dose separated by a 1-week washout. Plasma concentrations of gatifloxacin were determined by a validated high-performance liquid chromatography; pharmacokinetic parameters were calculated using noncompartmental methods. Distributions of pharmacokinetic parameter values were summarized by route of administration and gender. Effects of treatment on pharmacokinetic parameter values of gatifloxacin were assessed by an analysis of variance model suitable for a two-way, two-treatment, crossover design. Clinical evaluations were performed to assess drug safety and tolerability. MEASUREMENTS AND MAIN RESULTS: Intravenous and oral gatifloxacin were considered interchangeable because both routes were bioequivalent with respect to area under the curve (AUC; 90% confidence interval for the ratio of geometric means contained within 0.8-1.25). The plasma concentration-time profile after intravenous administration was similar and comparable in extent of exposure (AUC0-infinity) with that for the oral route when equal doses were administered to men and women. The absolute bioavailability of gatifloxacin after oral administration was 96%, consistent with bioequivalence of the 400-mg intravenous and oral doses. The drug was well tolerated; the frequency of adverse events was comparable after intravenous and oral administration. CONCLUSION: Intravenous and tablet formulations of gatifloxacin are bioequivalent and therefore interchangeable. This permits greater flexibility in choosing oral or parenteral therapy, with the possibility of avoiding hospitalization based on knowledge that oral administration will deliver therapeutic exposure to the drug, or abbreviating hospital stay due to ease of switching from intravenous to oral therapy.

Age and gender effects on the pharmacokinetics of gatifloxacin.

STUDY OBJECTIVE: To compare the pharmacokinetics and safety of gatifloxacin in elderly (> or = 65 yrs) and young (18-45 yrs) men and women. DESIGN: Open-label, parallel-group, single-dose study. SETTING: GFI Pharmaceutical Services Inc., Evansville, Indiana, USA. SUBJECTS: Forty-eight healthy subjects in four groups of 12 each. INTERVENTIONS: Subjects received single oral doses of gatifloxacin 400 mg. Serial blood and urine samples were collected for 96 hours after dosing to determine drug concentrations. MEASUREMENTS AND MAIN RESULTS: Age and gender had moderate effects on the pharmacokinetics of gatifloxacin. Elderly women had a 21% higher geometric mean peak plasma concentration (Cmax) and a 32% higher area under the plasma concentration-time curve (AUC0-infinity) than young women. Adjustment for creatinine clearance had only a slight effect on Cmax but reduced the estimated effect of age on AUC0-infinity in women from a 32% increase to a 15% increase. Gender effects on pharmacokinetic values were noted among elderly subjects only. Geometric means for Cmax and AUC0-infinity were 21% and 33% higher, respectively, for elderly women and elderly men. Adjustment for body weight reduced these differences to 11% and 20%, respectively. CONCLUSION: The effects of age on gatifloxacin pharmacokinetic values were largely attributed to declining renal function, whereas those of gender were largely attributed to differences in body weight. These modest age- and gender-related differences do not warrant dosage adjustment.

Safety and pharmacokinetics of a single oral dose of gatifloxacin in patients with moderate to severe hepatic impairment.

STUDY OBJECTIVES: To assess the safety and pharmacokinetics of oral gatifloxacin 400 mg in subjects with and without hepatic impairment, and the need to modify doses in patients with hepatic dysfunction. DESIGN: Single-dose, nonrandomized, open-label, parallel-group study. SETTING: Clinical Research Center, New Orleans, Louisiana. PATIENTS: Eight subjects with grade B or C hepatic dysfunction (Child-Pugh classification) and eight age-, weight-, and gender-matched subjects with normal hepatic function. INTERVENTIONS: After a single oral dose of gatifloxacin 400 mg, blood and urine samples were collected at specified times or intervals over 48 hours to determine drug concentrations. MEASUREMENTS AND MAIN RESULTS: All 16 subjects (7 with grade B and 1 with grade C hepatic impairment, 8 with normal hepatic function) completed the study. Peak plasma concentration (Cmax) and area under the plasma concentration-time curve (AUC0-infinity) for gatifloxacin were 32% and 22% higher, respectively, in subjects with hepatic impairment. Except for Cmax, the ratio of means for AUC satisfied the specified criterion (0.67-1.50) for lack of effect. There were no statistically significant differences in any other pharmacokinetic values except apparent oral clearance (ClT/F). All treatment-emergent adverse events were mild or moderate in intensity and resolved before subjects were discharged from the study. CONCLUSION: Modest increases in Cmax and AUC0-infinity are not anticipated to have a negative effect on the outcome of therapy in hepatically impaired subjects, nor are they anticipated to result in adverse drug reactions. Patients with moderate to severe (Child-Pugh grade B or C) hepatic dysfunction do not require gatifloxacin dose adjustments. In addition, the similarity in half-life (t1/2) for the groups (8.9 hrs for hepatically impaired subjects, 9.3 hrs for controls) suggests that no difference would be anticipated in the extent of drug accumulation after multiple doses. The overall safety and tolerability of a single oral dose of gatifloxacin 400 mg were excellent in both healthy subjects and those with hepatic impairment.

Effect of multiple-dose gatifloxacin or ciprofloxacin on glucose homeostasis and insulin production in patients with noninsulin-dependent diabetes mellitus maintained with diet and exercise.

STUDY OBJECTIVES: To compare the effects of gatifloxacin and ciprofloxacin on glucose homeostasis, including glucose tolerance test (GTT), pancreatic beta-cell function, and insulin production and secretion in patients with noninsulin-dependent (type 2) diabetes mellitus (NIDDM) maintained with diet and exercise; and to evaluate the pharmacokinetics, safety, and tolerability of gatifloxacin. DESIGN: Randomized, double-blind, placebo-controlled, multiple-dose study. SETTING: GFI Pharmaceutical Services, Inc., Evansville, Indiana; Chicago Center for Clinical Research, Chicago, Illinois; and New Orleans Center for Clinical Research, New Orleans, Louisiana, USA. PATIENTS: Forty-eight men and women with NIDDM. INTERVENTIONS: Patients were assigned sequentially at enrollment to receive gatifloxacin 400 mg/day orally, ciprofloxacin 500 mg twice/day orally, or placebo for 10 days. Oral GTTs were performed on specific days throughout the study, as well as measurements of serum glucose, serum insulin, and C-peptide levels. Physical examinations, electrocardiograms, spirometry, and clinical laboratory tests were performed before dosing and on selected dosing days. MEASUREMENTS AND MAIN RESULTS: Gatifloxacin had no significant effect on glucose tolerance and pancreatic beta-cell function, as shown by oral GTT results and insulin and C-peptide levels. Fasting glucose levels 0-6 hours after gatifloxacin administration on days 1 and 10 showed a downward trend, but it was not significant compared with placebo; results were similar with ciprofloxacin. Gatifloxacin also lacked a long-term effect on fasting insulin levels, but this was not shown for a short-term effect, suggesting a modest, transient effect on insulin release. On the other hand, ciprofloxacin had no short-term effect but produced a more sustained effect on insulin release and production. The pharmacokinetics of gatifloxacin in patients with NIDDM were similar to those in healthy subjects. Overall, subjects tolerated treatment well. All reported drug-related adverse events were mild to moderate in intensity. The frequency of adverse events was similar in gatifloxacin- and ciprofloxacin-treated patients, and only slightly higher than in placebo-treated patients. CONCLUSION: Gatifloxacin was well tolerated in patients with NIDDM controlled by diet and exercise. It had no significant effect on glucose homeostasis, beta-cell function, or long-term fasting serum glucose levels, but it did cause a brief increase in serum insulin levels.

Open-label, nonrandomized study of the effects of gatifloxacin on the pharmacokinetics of midazolam in healthy male volunteers.

STUDY OBJECTIVE: To confirm findings from an in vitro study that showed gatifloxacin did not substantially inhibit cytochrome P450 (CYP) 3A4 model substrate metabolism. DESIGN: Open-label, nonrandomized trial. SETTING: Clinical pharmacology unit. SUBJECTS: Fourteen healthy adult men. INTERVENTION: Using midazolam probe methodology, the clearance of midazolam in the presence of multiple-dose gatifloxacin was evaluated. MEASUREMENTS AND MAIN RESULTS: Typical steady-state concentrations of gatifloxacin 400 mg once/day had no effect on midazolam clearance, and gatifloxacin pharmacokinetics were unaffected by midazolam. All doses of both agents were well tolerated. CONCLUSION: Data from this in vivo trial support in vitro experience with gatifloxacin and suggest that interactions are unlikely between gatifloxacin and drugs that are metabolized by CYP3A.

Phase I study of the mitomycin C analogue BMS-181174.

BMS-181174 is an aminodisulphide derivative of Mitomycin C (MMC) with activity against a range of tumour cell lines and xenografts, including MMC-resistant tumours. In a phase I study of 82 patients with confirmed malignancy, we administered BMS-181174 at doses of 0.8-75 mg m(-2) by intravenous injection every 28 days. At least three patients were evaluated at each dose level, and 174 courses were administered. The pharmacokinetics were dose linear at BMS-181174 doses of 11.5-75 mg m(-2) and the drug appeared to undergo wide distribution. The maximum-tolerated dose was 65 mg m(-2) in previously treated patients and 75 mg m(-2) in chemotherapy-naive cases. The dose-limiting toxicity was myelosuppression, particularly thrombocytopenia, which was prolonged and cumulative. Three patients treated at 65-75 mg m(-2) died suddenly with evidence of pneumonia/pneumonitis, thought to be drug-related. Other toxicities included thrombophlebitis, possible cardiotoxicity (asymptomatic, reversible decline in left ventricular function) and renal impairment. The partial response rate was 5% (4 out of 82) overall, and 9% (3 out of 32) in patients treated at 65-75 mg m(-2). Responses occurred in treated and previously-untreated patients, including cases of colorectal cancer, non-small-cell lung cancer, ovarian cancer and adenocarcinoma of unknown primary site. BMS-181174 has anti-cancer activity but, because of its toxicity, particularly pneumonitis and thrombophlebitis, no phase II studies are planned.

Phase I trial of fluorouracil modulation by N-phosphonacetyl-L-aspartate and 6-methylmercaptopurine ribonucleoside (MMPR), and leucovorin in patients with advanced cancer.

The results of several clinical trials support the hypothesis that biochemical modulation may enhance the antitumor activity of 5-Fluorouracil (5-FU). We have performed a phase I trial using a combination of three different biochemical modulators at the optimal dose established in previous clinical trials. The modulators include: phosphonacetyl-l-aspartate (PALA), which may increase 5-FU incorporation into RNA; leucovorin, which potentiates thymidylate synthase inhibition; and 6-methylmercaptopurine riboside (MMPR), which promotes the intracellular retention of fluorinated nucleotides. The treatment regimen consisted of PALA 250 mg/m2 day 1, followed 24 h later by MMPR 150 mg/m2 as an iv bolus, and the initiation of a 24-hour infusion of 5-FU along with leucovorin 50 mg/m2. This regimen was repeated weekly. Doses of 5-FU were escalated in cohorts of four or more patients from 2,000 to 2,600 mg/m2. Among 20 patients entered, the majority had colorectal cancer, and most had received prior 5-FU treatment. Toxicity was predominantly gastrointestinal, and diarrhea was dose-limiting at a 5-FU dose of 2600 mg/m2. There were three partial remissions observed, two of whom had colorectal cancer. Emerging data that casts doubt on the modulation value of PALA at this dose and schedule suggests that revision of this regimen be considered before Phase II trial.

Phase I trial of buthionine sulfoximine in combination with melphalan in patients with cancer.

PURPOSE AND METHODS: Resistance to alkylating agents and platinum compounds is associated with elevated levels of glutathione (GSH). Depletion of GSH by buthionine sulfoximine (BSO) restores the sensitivity of resistant tumors to melphalan in vitro and in vivo. In a phase I trial, each patient received two cycles as follows: BSO alone intravenously (i.v.) every 12 hours for six doses, and 1 week later the same BSO as cycle one with melphalan (L-PAM) 15 mg/m2 i.v. 1 hour after the fifth dose. BSO doses were escalated from 1.5 to 17 g/m2 in 41 patients. RESULTS: The only toxicity attributable to BSO was grade I or II nausea/vomiting in 50% of patients. Dose-related neutropenia required an L-PAM dose reduction to 10 mg/m2 at BSO 7.5 g/m2. We measured GSH in peripheral mononuclear cells (PMN), and in tumor biopsies when available, at intervals following BSO dosing. In PMNs, GSH content decreased over 36 to 72 hours to reach a nadir on day 3; at the highest dose, recovery was delayed beyond day 7. The mean PMN GSH nadirs were approximately 10% of control at BSO doses > or = 7.5 g/m2; at 13 and 17 g/m2, all but two patients had nadir values in this range. GSH was depleted in sequential tumor biopsies to a variable extent, but with a similar time course. At BSO doses > or = 13 g/m2, tumor GSH was < or = 20% of starting values on day 3 in five of seven patients; recovery had not occurred by day 5. We measured plasma concentrations of R- and S-BSO by high-performance liquid chromatography (HPLC) in 22 patients throughout the dosing period. Total-body clearance (CLt) and volume of distribution at steady-state (Vss) for both isomers were dose-independent. The CLt of S-BSO was significantly less than that of R-BSO at all doses, but no significant differences in Vss were observed between the racemates. Harmonic mean half-lives were 1.39 hours and 1.89 hours for R-BSO and S-BSO, respectively. CONCLUSION: A biochemically appropriate dose of BSO for use on this schedule is 13 g/m2, which will be used in phase II trials to be conducted in ovarian cancer and melanoma.

Phase I trial of fluorouracil modulation by N-phosphonacetyl-L-aspartate and 6-methylmercaptopurine ribonucleoside.

Inhibition of pyrimidine and purine synthesis has been demonstrated to potentiate 5-fluorouracil (5-FU) activity in preclinical models. Low-dose phosphonacetyl-L-aspartate (PALA) potentiates the incorporation of 5-FU into RNA, without detectably increasing its toxicity. 6-Methylmercaptopurine riboside (MMPR) results in inhibition of purine biosynthesis with elevation of phosphoribosyl pyrophosphate (PRPP), which in turn is believed to increase the phosphorylation and intracellular retention of 5-FU. We conducted a phase I clinical trial to determine the maximum tolerated dose of 5-FU in combination with low-dose PALA and a biochemically-optimized dose of MMPR. The regimen consisted of PALA 250 mg/m2 given on day 1, followed 24 h later by MMPR 150 mg/m2, and escalating doses of 5-FU from 1625 to 2600 mg/m2 by 24 h continuous infusion. This regimen was repeated weekly. A group of 29 patients with a diagnosis of malignant solid tumor were entered; their median performance status was 1. The dose-limiting toxicity was mucositis, while other gastrointestinal toxicity was minimal. Two patients also experienced ischemic chest pain during the 5-FU infusion. The maximum tolerated dose of 5-FU in this combination was 2600 mg/m2. Several responses were observed including a complete remission in a previously treated breast cancer patient and two partial responses in breast and colon cancer. MMPR pharmacokinetics were obtained from urine analyses in 21 patients on this trial; there was no correlation between the pharmacokinetics of MMPR and the toxicity observed. This regimen was well tolerated and phase II trials are warranted using PALA 250 mg/m2, MMPR 150 mg/m2, and 5-FU 2300 mg/m2 by continuous infusion over 24 h.

Phase I study of phosphonacetyl-L-aspartate, 5-fluorouracil, and leucovorin in patients with advanced cancer.

Low-dose phosphonacetyl-L-aspartate (PALA) may potentiate both 5-fluorouracil (5-FU) incorporation into RNA and thymidylate synthase inhibition by 5-fluorodeoxyuridylate (5-FdUMP). The gastrointestinal toxicity of 5-FU is not increased by PALA administration. Exogenous leucovorin, on the other hand, which enhances thymidylate synthase inhibition, appears to increase the clinical toxicity of 5-FU in a dose-dependent manner. As a result, the clinical use of high-dose leucovorin requires a marked dose reduction of 5-FU. Extracellular leucovorin levels of 1 microM suffice to maximize the enhancement of thymidylate synthase inhibition in several models. We conducted a trial to add leucovorin to the PALA/5-FU regimen. We chose a leucovorin dose that was predicted to yield end-infusion total reduced folate concentrations of 1 microM. The major endpoint was to determine the maximum tolerated dose of 5-FU in this combination. The regimen consisted of 250 mg/m2 PALA given on day 1 and, 24 h later, escalating 5-FU doses ranging from 1,850 to 2,600 mg/m2 admixed with 50 mg/m2 leucovorin and given by 24-h infusion. Courses were repeated weekly. A total of 24 patients with a median performance status of 1 were entered at three dose levels. Diarrhea was dose-limiting; 6/13 patients had grade II or worse diarrhea at 2,600 mg/m2. Dose modification resulted in a mean dose intensity of 2,300 mg/m2 at both the 2,600- and 2,300-mg/m2 dose levels. The 2,300-mg/m2 dose is suitable for phase II testing of this regimen. Three patients (two with breast cancer and 1 with sarcoma) had a partial remission. We measured steady-state concentrations (Css) of 5-FU in 23 patients. The mean Css increased with dose from 0.738 to 1.03 micrograms/ml. Total body clearance did not vary with dose in this range. Patients with grade II or worse diarrhea had a higher mean Css (1.10 +/- 0.19) than those with grade O or I toxicity (0.835 +/- 0.25, P < 0.02). Total bioactive folates (bound and free) were measured using a biological assay. Pretreatment values ranged from 2 to 52 nM and were not predictive of toxicity. End-infusion (23-h) values were somewhat lower than predicted and ranged from 400 to 950 nM. The risk of diarrhea was positively correlated with end-infusion total folate values. In a logistic regression analysis, total folate values obtained at 23 h were a more powerful predictor of diarrhea than were 5-FU Css values.(ABSTRACT TRUNCATED AT 400 WORDS)

Stereoselective pharmacokinetics of L-buthionine SR-sulfoximine in patients with cancer.

Buthionine sulfoximine (BSO) is an inhibitor of glutathione synthesis that can deplete intracellular glutathione and reverse resistance to platinating and alkylating agents in vitro and in vivo. We are performing a phase I study of BSO in combination with melphalan. The BSO used in this study was provided by the National Cancer Institute and is a mixture of the R- and S-diastereomers of L-BSO. We developed a reversed-phase HPLC assay to quantitate levels of the R- and S-BSO isomers in plasma and urine. The pharmacokinetics of BSO was determined in 11 patients: 3 patients at 5 g/m2, 4 patients at 7.5 g/m2, and 4 patients at 10.5 g/m2. Plots of plasma area under the concentration-time curve vs. dose for both R-BSO (r2 = 0.798) and S-BSO (r2 = 0.752) are linear, indicating linear pharmacokinetics in this dose range. However, the individual BSO isomers exhibit stereoselective disposition and elimination. Values for steady-state volume of distribution and renal clearance were similar for both isomers, but total clearance, nonrenal clearance, and half-life were approximately 25% different, with the R-(inactive) isomer being eliminated faster (higher clearance and shorter half-life) than the S- (active) isomer. Using a paired t test, we found that the pharmacokinetic parameters, total clearance, nonrenal clearance, and half-life for R-BSO were significantly different (p < 0.05) from those for S-BSO. Renal clearance of both S- and R-isomers approximated glomerular filtration rate and accounted for 64% of S-BSO total clearance and 56% of R-BSO total clearance.(ABSTRACT TRUNCATED AT 250 WORDS)

Pharmakokinetics and bioavailability study of ethacrynic acid as a modulator of drug resistance in patients with cancer.

Ethacrynic acid (EA) is an inhibitor of the glutathione S-transferases (GSTs), a family of detoxification enzymes the expression of which has been associated with resistance to several classes of anticancer drugs. We performed a two-way randomized crossover study to investigate the pharmacokinetics and bioavailability of EA and describe any toxicities of EA associated with i.v. administration. We administered EA (100 mg) either by the p.o. or i.v. route on days 1 and 2 for pharmacokinetic analysis. After i.v. administration, plasma EA disappearance was biphasic in seven patients and monophasic in two patients with a terminal half-life of 30 and 8 min, respectively. Mean total body clearance was high; 1405 ml/min in patients described by using a one-compartment model and 611 ml/min in those patients described by a two-compartment model. After p.o. administration, peak EA plasma concentrations were less than 10% of i.v. EA and the absolute bioavailability was less than 21% (range, 7-35%). The urinary output as a result of EA treatment was equal following either route of administration and together with the large first-pass effect suggests that a metabolite(s) may be the active diuretic agent(s). Burning at the injection site was the only toxicity unique to the i.v. route of EA administration. We concluded that the systemic availability of EA after p.o. administration is low and variable. This finding supports the potential utility of the i.v. route of administration for the treatment of drug resistance.

Phase I/pharmacokinetic study of topotecan by 24-hour continuous infusion weekly.

Topotecan (SK&F 104864, hycamptamine, NSC 609699) is believed to exert its cytotoxic effects through inhibition of topoisomerase I, the activity of which recovers rapidly on removal of the drug in vitro. In vivo studies show that the activity of topotecan is schedule dependent, favoring repeated doses. Early human studies showed that topotecan (the active lactone) had a short half-life in plasma. To prolong drug exposure, we administered topotecan as a 24-h i.v. infusion and repeated it weekly. We treated 32 patients with doses of 1.0-2.0 mg/m2. Median performance status was 1, and all but four patients had received prior chemotherapy. Dose-limiting neutropenia occurred at doses > or = 1.75 mg/m2; nadirs were observed after 1-3 doses. The recommended phase II dose is 1.5 mg/m2/week. One patient with metastatic colon cancer had a partial response. Both plasma topotecan (lactone) and total topotecan (measured by converting the hydroxyacid form to the lactone by acidification of the sample) were measured by high-performance liquid chromatography in 21 patients. During infusion, mean topotecan plasma steady-state concentrations ranged from 4.7-11.4 nM. Plasma elimination was best fit to a one-compartment model with a mean t1/2 of 3.5 h. The mean total body clearance was 388 ml/min/m2. Concentrations of the inactive form approximated those of the lactone throughout. No evidence for dose-dependent pharmacokinetics was observed in this dose range. Pharmacodynamic analysis, using the sigmoid Emax model, revealed that the pharmacokinetic parameters of both lactone and total drug were positively correlated with bone marrow toxicity. Total drug steady-state plasma concentration provided a good estimate of neutropenia, suggesting a simple, easily monitored, pharmacokinetic parameter for adaptive dosing using this schedule. Phase II evaluation of this weekly schedule is indicated in solid tumors.