Elora Gupta

Pharmacokinetic and pharmacodynamic evaluation of the topoisomerase inhibitor irinotecan in cancer patients

PURPOSE We conducted a pharmacokinetic and pharmacodynamic evaluation of irinotecan (CPT-11) and determined the effect of race and sex on disposition and toxicity of CPT-11. We tested the efficacy of acetaminophen (AAP) to phenotype SN-38 glucuronidation. PATIENTS AND METHODS Forty patients received a dose of 145 mg/m2 of CPT-11 as a 90-minute infusion. Total CPT-11, SN-38, and SN-38G were quantitated in plasma and urine samples. Following administration of 1 g AAP, urinary concentrations of AAP and AAP-glucuronide (AAP-G) were assessed. RESULTS CPT-11 exhibited a mean elimination half-life (t1/2) of 8.8 hours, an average clearance (CL) of 14.6 L/h/m2, and a mean volume of distribution at steady-state (Vdss) of 136 L/m2. SN-38 and SN-38G had low plasma availabilities (3% and 10% relative to CPT-11), with mean t1/2 values of 11.6 and 10.5 hours, respectively. Urinary recovery accounted for 15% of the dose. Race and sex had no effect on the plasma availability of CPT-11, SN-38, and SN-38G. The applicability of biliary index (BI) in predicting dose-limiting intestinal toxicity was validated. Patients who developed grade 3 or 4 toxicity had significantly higher index values compared with patients with grade 0 to 2 toxicity (P = .001). There was no difference in the incidence and severity of toxicity based on race and sex. AAP was a poor predictor of SN-38 glucuronidation. CONCLUSION The high degree of interpatient variability in parameter estimates suggests pharmacogenetic variation or differential induction or inhibition of the sequential metabolic pathway of CPT-11, as well as variability in transport systems. The low urinary recovery indicates substantial biliary excretion and supports the significant correlation between intestinal toxicity and BI. Black patients are not at increased risk of toxicity. An assessment of individual differences in SN-38 conjugation remains to be established.

Cancer Drug Discovery and Development

A significant amount of clinical research has been conducted with small molecules that inhibit matrix metalloproteinases (MMP), metal-containing enzymes that degrade the extracellular matrix and are implicated in tumor progression and angiogenesis (1–3). The majority of matrix metalloproteinase inhibitors (MMPIs) are designed with a concept similar to protease inhibitors used in the treatment of acquired immunodeficiency syndrome. MMPIs are currently under development for the treatment of a variety of diseases most notably cancer (3). Unlike conventional chemotherapy or radiation therapy, MMPIs are expected to slow tumor growth and prolong survival without causing detectable shrinkage of tumors. Because MMPIs are predicted to slow tumor growth but not shrink tumors, clinical development is not guided purely by objective tumor responses; proving the therapeutic value of these molecules will therefore require randomized placebo-controlled trials with assessment of the impact of drug treatment compared to placebo. Proof that these compounds are effective cytostatic agents will require demonstrating a survival advantage when compared to a placebo in a randomized, controlled trial.

Modulation of glucuronidation of SN-38, the active metabolite of irinotecan, by valproic acid and phenobarbital

Abstract Purpose: Irinotecan (CPT-11) is hydrolyzed to its active metabolite SN-38 which is subsequently conjugated by uridine diphosphate glucuronosyl transferase (UDP-GT) to the glucuronide (SN-38G). Both preclinical and clinical data indicate that conjugation is a primary clearance mechanism for SN-38 with the plasma glucuronide levels being substantially higher than those of SN-38. This investigation was designed to determine the possibility of modulation of glucuronidation of SN-38 and its effect on the disposition of the parent drug and metabolites. Methods: Female Wistar rats were pretreated with 200 mg/kg valproic acid (VPA), an inhibitor of glucuronidation, 5 min prior to the administration of 20 mg/kg irinotecan. The control rats were given 20 mg/kg irinotecan only. To study the effect of inducers of UDP-GT activity, rats were pre- treated with phenobarbital (PB) before irinotecan administration. Results: Pretreatment with VPA caused a 99% inhibition in the formation of SN-38G leading to a 270% increase in the area under plasma concentration-time curve (AUC) of SN-38 compared with the control rats. The irinotecan estimations were unchanged in the two groups. PB pretreatment caused a 1.7-fold increase in the AUC of SN-38G and a concomitant 31% and 59% reduction in the AUCs of SN-38 and irinotecan, respectively. Conclusions: The most plausible explanation for the alterations in SN-38G disposition is inhibition of SN-38 conjugation by VPA and induction of the conjugation by PB.

Limited-sampling models for irinotecan pharmacokinetics-pharmacodynamics: prediction of biliary index and intestinal toxicity.

PURPOSE To construct limited-sampling models (LSMs) for irinotecan (CPT-11) pharmacokinetic (PK) measures. MATERIALS AND METHODS The recommended phase II dose of weekly CPT-11 administered as a 90-minute infusion is 145 mg/m2 with granulocyte colony-stimulating factor (G-CSF) and maximal antidiarrheal support. Diarrhea is the dose-limiting toxicity. Previously, we demonstrated a highly significant correlation between severity of diarrhea and biliary index (BI), the estimated biliary exposure of SN-38. BI was the product of total CPT-11 area under the concentration-time curve (AUC) and the relative area ratio of SN-38 to SN-38 glucuronide (SN-38G). At 145 mg/m2, PK data were available for 40 patients; 36 were also assessable for intestinal toxicity. Total plasma concentrations of CPT-11, SN-38, and SN-38G from 1.0 to 11.5 hours from the start of the infusion were evaluated. CPT-11 concentration at each time point, t, is denoted by CPT-11t. LSMs were constructed by stepwise linear regression, on a training set (n = 25), and were validated on a test set (n = 15). RESULTS LSMs for CPT-11, SN-38, and SN-38G AUCs displayed excellent fit to the training set (R2 = .87, 0.75, and .98, respectively). AUCCPT-11 = 5.25 x CPT-11(3.0) + 20.60 x CPT-11(11.5) + 1,520.53; AUCSN-38 = 5.38 x SN-38(3.5) + 33.61 x SN-38(11.5) - 7.73; and AUCSN-38G = 10.73 x SN-38G9.5 + 20.66 x SN-38G11.5 + 142.69. BI at each time point (denoted BIt) was calculated as CPT-11t x (SN-38t/SN-38Gt). Several promising LSMs were defined by BI3.5 paired with BI7.5 (R2 = .63) or BI9.5 (R2 = .76), or BI5.5 paired with BI9.5 (R2 = .76). Predicted BI from each model (categorized into low, intermediate, or high) accurately predicted observed intestinal toxicity grade (P < or = .005). CONCLUSION These LSMs appear to accurately predict PK parameters of CPT-11. Notably, BI, predicted from several LSMs, accurately predicted intestinal toxicity and thus may be useful for future trials that use adaptive control with feedback.

Population pharmacokinetic model for irinotecan and two of its metabolites, SN‐38 and SN‐38 glucuronide

The objective of the study was to develop and validate a population pharmacokinetic model for irinotecan and 2 of its metabolites, SN‐38 and SN‐38 glucuronide (SN‐38G).

A Phase I Study of Oral BMS-275291, a Novel Nonhydroxamate Sheddase-Sparing Matrix Metalloproteinase Inhibitor, in Patients with Advanced or Metastatic Cancer

Purpose: BMS-275291 is a novel broad-spectrum inhibitor of matrix metalloproteinase (MMPs) rationally designed to spare a class of closely related metalloproteinases known as sheddases. Inadvertent sheddase inhibition is hypothesized to play a role in the dose-limiting joint toxicities occurring with hydroxamate-based MMP inhibitors. This trial was conducted to establish the recommended phase II dose; determine safety, toxicity, and pharmacokinetics of BMS-275291; and to assess potential markers of sheddase activity [tumor necrosis factor-α (TNFα) release and TNFα-RII shedding]. Experimental Design: This was an open label, single arm, phase I study conducted at two centers. Patients with advanced or metastatic cancer were treated with once-daily oral BMS-275291 at doses escalating from 600 to 2400 mg/day. Six to eight patients/dose level were to be studied with the recommended phase II dose level expanded to a total of 15 patients. Pharmacokinetic sampling was performed on days 1, 15, and 29 at 0, 0.5, 1, 2, 4, 6, 8, and 24 h after dosing. Radiological tumor assessment was performed every 8 weeks. Results: Forty-four evaluable patients were enrolled in this study with the most frequent tumor types being colorectal cancer and non-small cell lung cancer. Dose limiting toxicities were observed at 600 mg/day (one of eight patients with grade 3 transaminitis) and at 1200 mg/day (1 of 15 patients with grade 3 rash and grade 4 shortness of breath), both in the context of predisposing conditions. No dose-limiting toxicities occurred at 900, 1800, or 2400 mg/day. The most frequent adverse events considered possibly, probably, or definitely drug-related were joint toxicity (myalgia/arthralgia), rash, fatigue, headache, nausea, and taste change, all of which were mild, grade 1, grade 2, and not dose-limiting. No objective tumor responses were observed. Twelve of forty-four patients received treatment for 4+ months, six for 8+ months, three for >1 year. Desired trough levels of parent BMS-275291 were maintained with once daily dosing. The mean plasma concentration of parent BMS-275291 at trough exceeded the calculated in vitro IC80 value for MMP-2 and IC90 value for MMP-9 at the recommended phase II dose of 1200 mg/day. No major changes in serum concentrations of sheddase enzymatic products, TNFα or TNFα-RII, were observed. Conclusions: BMS-275291 is a nonhydroxamate MMP inhibitor with a novel mercaptoacyl zinc-binding group. In this study, plasma concentrations of BMS-275291 continuously exceeded in vitro MMP IC50 values without dose-limiting joint toxicity. In this refractory patient population, a suggestion of disease stabilization was observed in 12 patients. On the basis of preclinical, clinical, and pharmacokinetic data, the recommended phase II dose for future study is 1200 mg/day.

Phase I and Pharmacokinetic Study of BMS-184476, a Taxane With Greater Potency and Solubility Than Paclitaxel

PURPOSE To assess the feasibility, toxicity, pharmacokinetics, and preliminary activity of BMS-184476 administered as a 1-hour intravenous (IV) infusion every 3 weeks. PATIENTS AND METHODS Patients with advanced solid malignancies were treated with escalating doses of BMS-184476 as a 1-hour IV infusion every 3 weeks without premedication to prevent hypersensitivity reactions (HSR). Plasma sampling and urine collections were performed to characterize the pharmacokinetics and pharmacodynamics of BMS-184474. RESULTS Thirty-four patients were treated with 78 courses of BMS-184476 at five dose levels ranging from 20 to 80 mg/m2. Dose-limiting toxicity (DLT), consisting of severe neutropenia with fever, severe diarrhea, and/or severe mucositis, was experienced during course 1 by six of nine minimally pretreated patients treated at the 70 and 80 mg/m2 dose level. In contrast, of 15 assessable patients treated at the 60 mg/m2 dose level, which is the maximum-tolerated dose (MTD) of BMS-184476 on this administration schedule, only one heavily pretreated patient developed DLT (grade 4 neutropenia with fever and grade 3 diarrhea). One patient developed a grade 2 HSR during a second course of BMS-184476 at the 40 mg/m2 dose level. A previously untreated patient with an advanced cholangiocarcinoma experienced a partial response, and a patient with an untreated carcinoma of the gastroesophageal junction had a minor response. The pharmacokinetics of BMS-184476 seemed linear in the dose range studied. Mean +/- SD values for clearance, volume of distribution at steady-state, and terminal half-life were 220 +/- 89 mL/min/m2, 402 +/- 231 L/m2, and 40.8 +/- 21.8 hours, respectively. CONCLUSION The MTD and recommended dose for phase II evaluations of BMS-184476 is 60 mg/m2 as a 1-hour IV infusion every 3 weeks. The results of this study suggest that BMS-184476 may have several advantages compared with paclitaxel in terms of toxicity, pharmacokinetics, pharmaceutics, and administration and warrants further clinical development.

A pharmacokinetic (PK) model for irinotecan and its metabolites in cancer patients

Clinical Pharmacology & Therapeutics (1999) 65, 197–197; doi:

Pharmacokinetic-pharmacodynamic (PK-PD) analysis of intestinal toxicity associated with irinotecan (CPT-11): validation of biliary index (BI)

Clinical Pharmacology & Therapeutics (1996) 59, 197–197; doi: 10.1038/sj.clpt.1996.289