Tom Verhaeghe

Phase II and pharmacodynamic study of the farnesyltransferase inhibitor R115777 as initial therapy in patients with metastatic pancreatic adenocarcinoma.

PURPOSE R115777 is a selective nonpeptidomimetic inhibitor of farnesyltransferase (FTase), one of several enzymes responsible for posttranslational modification that is required for the function of p21(ras) and other proteins. Given that RAS mutations are nearly universal in pancreatic cancer and R115777 demonstrated preclinical activity against pancreatic cell lines and xenografts, this phase II study was undertaken to determine its clinical activity and effect on target proteins in patients with measurable metastatic pancreatic adenocarcinoma. PATIENTS AND METHODS Twenty patients who had not received prior therapy for metastatic disease were treated with 300 mg of R115777 orally every 12 hours for 21 of 28 days. Inhibition of FTase activity in peripheral-blood mononuclear cells was measured using a lamin B C-terminus peptide as substrate. Western blot analysis was performed to monitor farnesylation status of the chaperone protein HDJ-2. RESULTS No objective responses were seen. Median time to progression was 4.9 weeks, and median survival time was 19.7 weeks. The estimated 6-month survival rate was 25%, with no patients progression-free at 6 months. Grade 3/4 toxicities were liver enzyme elevation, anemia, neutropenia, thrombocytopenia, fatigue, nausea/vomiting, rash, and anorexia. FTase activity (mean +/- SD) decreased by 49.8% +/- 9.8% 4 hours after treatment on day 1 and 36.1% +/- 24.8% before treatment on day 15. HDJ-2 farnesylation (mean +/- SD) decreased by 33.4% +/- 19.8% on day 15. CONCLUSION Although treatment with R115777 resulted in partial inhibition of FTase activity in mononuclear cells, it did not exhibit single-agent antitumor activity in patients with previously untreated metastatic pancreatic cancer.

Development and validation of a liquid chromatographic-tandem mass spectrometric method for the determination of galantamine in human heparinised plasma.

Galantamine is an acetylcholinesterase inhibitor, recently approved for the treatment of mild-to-moderate Alzheimers disease. To allow a higher throughput of samples, a new bioanalytical method for the determination of galantamine in human plasma was developed and validated. A stable isotope labelled internal standard was used. Sample preparation consisted of a simple one-step liquid-liquid extraction with toluene. The extracts were analysed with positive ion TurboIonspray tandem mass spectrometry (LC-MS-MS). The method was validated in the 1-500-ng/ml range. The accuracy, precision, selectivity, lower limit of quantification, upper limit of quantification, linearity and extraction recovery were evaluated, as well as the stability of the compound in plasma, blood, methanol and 2% BSA solutions under different conditions. The method proved very rugged during the analysis of large numbers of samples from clinical trials.

Pharmacokinetic Interaction Study between the New Antiepileptic and CNS Drug RWJ-333369 and Carbamazepine in Healthy Adults

Summary:  Purpose: To characterize the possible pharmacokinetic interaction between the new antiepileptic and CNS drug RWJ‐333369 and carbamazepine (CBZ) following multiple dosing in healthy subjects.

Steady‐State Pharmacokinetics of Galantamine Are Not Affected by Addition of Memantine in Healthy Subjects

To evaluate the effect of multiple doses of memantine on the pharmacokinetics of galantamine and to assess the safety and tolerability of galantamine with adjunctive memantine treatment, an open‐label, single‐center, drug interaction study was conducted in 16 healthy adults. Subjects received an 8‐mg dose of galantamine extended release once daily during week 1 and a 16‐mg dose of galantamine extended release once daily during week 2. During weeks 3 and 4, they received a 16‐mg dose of galantamine extended release once daily and a 10‐mg dose of memantine twice daily, except on days 1 and 2 of week 3, when memantine was given as 10 mg once daily. The pharmacokinetic profile and parameters of galantamine at steady state were similar after administration of a 16‐mg dose of galantamine once daily alone and after administration with a 10‐mg dose of memantine twice daily. Galantamine 16 mg once daily with adjunctive memantine 10 mg twice daily was well tolerated and safe in healthy subjects.

Pharmacokinetics and Safety of Galantamine in Subjects with Hepatic Impairment and Healthy Volunteers

The objective of this study was to compare the pharmacokinetics and safety of galantamine in subjects with hepatic impairment with those in healthy subjects. This was an open‐label study in which a single oral 4‐mg dose of galantamine was administered to volunteers with mild (Child‐Pugh score of 5–6, n = 8), moderate (Child‐Pugh score of 7–9, n = 8), or severe hepatic impairment (Child‐Pugh score of 10–15, n = 1) and to healthy, matched control subjects (n = 8). Galantamine pharmacokinetics and safety (adverse events, laboratory test results, electrocardiograms, vital signs, and cardiac events) were assessed over 6 days after administration of galantamine. The pharmacokinetic parameters of galantamine were similar in subjects with mild hepatic impairment compared with healthy controls. Compared with the healthy control group, subjects with moderate hepatic impairment showed relative increases in the area under the plasma‐concentration curve from zero to infinity (AUC0∞_J (+33%) and terminal half‐life (t1/2) (+30%) (p = 0.051 and p = 0.003, respectively), a 23% relative decrease in total plasma clearance (p = 0.061), and a small but significant relative increase in the fraction of free plasma galantamine (p = 0.009). Galantamine was well tolerated by all subjects. There were no serious adverse events (AEs) or premature withdrawals from the study because of AEs. Reported AEs were headache (three cases), nausea (one case), and paresthesia (one case). There were no clinically relevant changes in clinical laboratory findings, vital signs, and electrocardiograms. Low patient recruitment (n = 1) precluded statistical analysis of galantamine pharmacokinetics and safety in severe hepatic impairment. It was concluded that the pharmacokinetics of galantamine in subjects with mild hepatic impairment was similar to those in healthy subjects. In subjects with moderate hepatic impairment, galantamine clearance was decreased by approximately 23% compared with normal volunteers. Galantamine was also well tolerated and appeared to be safe in subjects with mild or moderate hepatic impairment. Based on the study results, it appears that it would not be necessary to adjust doses of galantamine during administration to subjects with mild hepatic impairment. In subjects with moderately impaired hepatic function, dose titration should proceed cautiously. Unfortunately, difficulties with patient recruitment did not allow adequate assessment of the safety of galantamine in subjects with severe hepatic impairment in this study. Therefore, the use of galantamine in subjects with severe hepatic impairment is not recommended.

Pharmacokinetic and Safety Assessments of Galantamine and Risperidone after the Two Drugs Are Administered Alone and Together

To explore the steady‐state pharmacokinetic profile after coadministration of galantamine and risperidone, an open‐label, randomized, single‐center, two‐way crossover drug‐drug interaction study was conducted in 16 healthy elderly subjects, ages 60 years and older. The results showed that risperidone, when administered with galantamine, did not change the bioavailability of galantamine at steady state. In addition, systemic exposure of risperidone active moiety (risperidone plus 9‐hydroxyrisperidone), the most clinically relevant component of risperidone treatment, was not affected by galantamine coadministration, while systemic exposure was increased by approximately 10% for risperidone and decreased by about 10% for 9‐hydroxyrisperidone (active metabolite of risperidone). Galantamine and risperidone were both safe and well tolerated administered either alone or together. Thus, no dose adjustment for either risperidone or galantamine is necessary when these two drugs are administered together in the dose range evaluated.

Pharmacokinetics of extended-release and immediate-release formulations of galantamine at steady state in healthy volunteers

ABSTRACT Objective: To assess the steady-state galantamine (GAL) bioavailability of the extended-release 24‐mg qd capsule (GAL‐ER) with and without food and to evaluate the relative bioavailability of GAL‐ER with the immediate-release 12‐mg bid tablet (GAL‐IR) at steady state. Methods: This was a single-center, open-label, randomized, 3-way crossover study in 24 healthy volunteers (12 males and 12 females) aged 18 to 45 years. After 7 days of GAL‐ER 8 mg qd each morning and 7 days of GAL‐ER 16 mg qd each morning, subjects received the following treatments in randomized, crossover order (7 days each): GAL‐ER 24 mg qd each morning (fasted before Day 7 morning dose), GAL‐ER 24 mg qd each morning (fed before Day 7 morning dose), and GAL‐IR 12 mg bid (fasted before Day 7). Pharmacokinetic parameters of GAL at steady state were determined after morning intake on Day 7 of each treatment week. Safety evaluations included adverse event (AE) reporting, physical examination, clinical laboratory tests, vital signs, and electrocardiography. Results: The treatment ratios of area under the plasma concentration-time curve of GAL from time 0–24 h post-dosing (AUC24 h), peak plasma concentration (Cmax), and pre-dose plasma concentration (Cmin) for GAL‐ER fed/fasting were 105%, 112%, and 103%, respectively. The treatment ratios and 90% confidence intervals for all above mentioned pharmacokinetic parameters demonstrated bioequivalence (with the range of 80-125%), indicating that food had no effect on GAL‐ER bioavailability. As anticipated, GAL‐ER (fasting) had mean AUC24 h similar to GAL‐IR (fasting), with lower Cmax (63 ng/mL vs 84 ng/mL) and longer time to reach Cmax (4.4 h vs 1.2 h). The treatment ratios and 90% confidence intervals for both AUC24 h and Cmin demonstrated bioequivalence (within the range of 80-125%). The treatment ratio for Cmax was 75.7%, indicating a 24% lower Cmax for GAL‐ER than for GAL‐IR. In this study, GAL‐ER was safe and well tolerated with or without food and was comparable to the GAL‐IR formulation. Conclusion: Food had no effect on the GAL bioavailability of GAL‐ER at steady state. GAL‐ER was bioequivalent to GAL‐IR with respect to AUC24 h and Cmin.

An interaction study between the new antiepileptic and CNS drug carisbamate (RWJ-333369) and lamotrigine and valproic acid.

Summary:  Purpose: To characterize possible pharmacokinetic interactions between the new antiepileptic drug carisbamate (RWJ‐333369) and valproic acid (VPA) or lamotrigine (LTG) following multiple dosing in healthy subjects.

The application of capillary microsampling in GLP toxicology studies

AIM Capillary microsampling (CMS) to collect microplasma volumes is gradually replacing traditional, larger volume sampling from rats in GLP toxicology studies. METHODOLOGY About 32 µl of blood is collected with a capillary, processed to plasma and stored in a 10- or 4-µl capillary which is washed out further downstream in the laboratory. CMS has been standardized with respect to materials, assay validation experiments and application for sample analysis. CONCLUSION The implementation of CMS has resulted in blood volume reductions in the rat from 300 to 32 µl per time point and the elimination of toxicokinetic satellite groups in the majority of the rat GLP toxicology studies. The technique has been successfully applied in 26 GLP studies for 12 different projects thus far.

Pharmacokinetics of Tipifarnib After Oral and Intravenous Administration in Subjects With Advanced Cancer

The primary objective of this study was to identify intravenous regimens of tipifarnib that would mimic the systemic exposure obtained after the current twice‐daily oral administration of tipifarnib. After determination of an intravenous dose that 6 subjects with advanced cancer could tolerate, another 26 subjects were randomly assigned to receive 3 consecutive 4‐day regimens of tipifarnib with different treatment sequences: a 100‐mg 2‐hour intravenous infusion, 200‐mg oral administration twice daily, and a 200‐mg/d continuous intravenous infusion. The systemic exposure to tipifarnib was comparable among these 3 regimens. The plasma concentration‐time profile of 2‐hour intravenous infusion more closely resembled the oral administration than did the continuous infusion. Glucuronidation is a metabolic pathway for tipifarnib with concentrations of the glucuronide conjugate greatly exceeding the parent compound after oral and intravenous administration. Analysis of plasma metabolites indicated that tipifarnib also undergoes dealkylation and loss of the imidazole group.