Adenosine A2A receptor antagonist istradefylline (KW-6002) reduces "off" time in Parkinson's disease: a double-blind, randomized, multicenter clinical trial (6002-US-005).

OBJECTIVE: Based on new understanding of nondopaminergic pathways involved in Parkinson's disease (PD) pathophysiology, a selective adenosine A(2A) receptor antagonist, istradefylline, shows promise for the treatment of PD. METHODS: Istradefylline (40mg/day) was studied in levodopa-treated PD subjects experiencing prominent wearing-off motor fluctuations. At 23 North American sites, 196 subjects were randomized in a double-blind, 12-week outpatient clinical trial of istradefylline (114 completing the trial) or placebo (58 completing the trial). The primary efficacy measure was change from baseline to end point in the percentage of daily awake "off" time, recorded by subjects using a patient PD diary. Secondary end points evaluated "on" time (including "on time with dyskinesia"), the Unified Parkinson's Disease Rating Scale, and a Clinical Global Impression-Improvement of Illness score. Clinical laboratory, electrocardiograms, vital signs, and adverse event monitoring comprised the safety monitoring. RESULTS: After randomization, approximately 88% of subjects completed the double-blind period. Compared with baseline, the decrease of daily awake "off" time for istradefylline was a mean (+/- standard deviation) of -10.8 +/- 16.6% (95% confidence interval, -13.46 to -7.52) and for placebo, -4.0 +/- 15.7% (95% confidence interval, -7.73-0.31; p = 0.007 using two-way analysis of variance). This effect corresponded to changes from baseline in total daily awake "off" time of -1.8 +/- 2.8 hours for istradefylline and -0.6 +/- 2.7 hours for placebo (p = 0.005). Treatment-emergent adverse effects with istradefylline were generally mild. INTERPRETATION: Istradefylline was safe, well tolerated, and offered a clinically meaningful reduction in "off" time without increased troublesome dyskinesia.

Pharmacokinetics of Lapatinib, a Nonrenally Cleared Drug, in Patients With End-Stage Renal Disease on Maintenance Hemodialysis.

Lapatinib, a tyrosine kinase inhibitor, is approved for the treatment of breast cancer. The literature shows that it is metabolized by CYP3A4 and eliminated predominantly (>90%) by the fecal route, with minimal (<2%) renal elimination in healthy subjects (dose of 250 mg); in cancer patients, renal elimination is minimal at therapeutic doses. For nonrenally cleared drugs, while there is ample evidence of pharmacokinetic alterations secondary to renal impairment-induced effects on drug metabolizing enzymes and/or transporters, the effect of end-stage renal disease (ESRD) on lapatinib pharmacokinetics has not been determined. Rather, as stated in the drug's label, the expectation is lack of effect of renal impairment on lapatinib pharmacokinetics based on its minimal renal elimination. The current report addresses this gap with pharmacokinetic data (obtained in a 1-way drug interaction study) in ESRD patients (n = 11) on maintenance hemodialysis and compared with published data in 37 healthy subjects in 3 separate studies. Following a 250-mg oral dose in ESRD patients, the median tmax was 3.0 hours, and geometric mean (95%CI) values for Cmax , AUCinf , and t1/2 were 349 ng/mL (245-499 ng/mL), 4410 ng·h/mL (2960-6580 ng·h/mL), and 14.8 hours (9.7-22.5 hours), respectively. These parameters approximated published values in healthy subjects and demonstrated that renal impairment and hemodialysis did not affect lapatinib pharmacokinetics. The results of the present study in this renally impaired population, the only such information available to date, support the drug's label and are valuable in view of the recognized difficulties in enrolling organ-impaired patients in oncology trials.

Core Entrustable Professional Activities in Clinical Pharmacology for Entering Residency: Common Problem Drugs and How to Prescribe Them.

Although the medical profession strives for safe prescribing, most medications are unique challenges even when prescribed by an experienced provider. In this article we discuss the pitfalls associated with drug interactions between commonly used antibiotics and anticoagulants, the complexities associated with the administration of novel reversible anticoagulants, the often-overlooked severe adverse drug reactions from commonly used classes of medications such as corticosteroids, the nuances of managing an acetaminophen overdose, and uncommon yet serious adverse events associated with the use of contraceptive hormone drugs.

Hemangiosarcoma in a Dog: Unusual Presentation and Increased Survival Using a Complementary/Holistic Approach Combined with Metronomic Chemotherapy.

This case report documents the clinical and pathologic findings in a 12-year-old terrier mix with intraocular and splenic hemangiosarcoma. Pathologic findings in both the spleen and globe were consistent with hemangiosarcoma with a low mitotic count. Initial treatment consisted of enucleation and then splenectomy followed by one cycle of conventional doxorubicin chemotherapy. Due to poor tolerance, a subsequent treatment regimen consisted of metronomic chemotherapy with chlorambucil combined with an alternative/complementary regimen of I'm-Yunity (polysaccharopeptide) and Yunnan Baiyao. Follow-up thoracic radiographs and abdominal ultrasounds over a period of 24 months showed no evidence of pulmonary, hepatic, or right atrial metastases, during which time the patient had an excellent quality of life. However, shortly after achieving two-year survival, the patient developed new onset seizures unresponsive to anticonvulsant therapy. Therefore, a decision was made to euthanize the dog given that the most likely etiology of the seizures was a brain tumor. Overall, this is an exceptional treatment response given the poor survival statistics of hemangiosarcoma even with conventional chemotherapy. However, additional clinical pharmacology and clinical trial data are needed to further support the use of a complementary/holistic approach in combination with metronomic chemotherapy.

The Bial 10-2474 Phase 1 Study-A Drug Development Perspective and Recommendations for Future First-in-Human Trials.

BIA 10-2474 (a fatty acid amide hydrolase inhibitor) was evaluated in a first-in-human phase 1 study in normal volunteers to assess safety/tolerability, pharmacokinetics, pharmacodynamics, and food effect. The dose-escalation process consisted of a single-ascending-dose phase (SAD) and multiple-ascending-dose phase (MAD). Prospective determination of the starting dose and maximal escalated dose was consistent with the usual clinical pharmacology principles for extrapolation of preclinical toxicology data to human equivalent doses. After only 5-6 days of multiple-dose administration of 50 mg daily in the MAD phase, several subjects became quite ill with central nervous system symptoms. One subject progressed to brain death within several days of symptom onset. Magnetic resonance imaging scans demonstrated signal abnormalities consistent with microbleeds affecting the hippocampus and pons, suggestive of possible cytotoxic or vasogenic edema compatible with a toxic/metabolic process. There were no findings at lower MAD doses or during the SAD phase. The toxicology program carried out in 4 preclinical species (mouse, rat, dog, and monkey) did not demonstrate significant neurotoxicity. The probable mechanism of neurologic toxicity demonstrated in humans at the 50-mg daily dose was inhibition of off-target cerebral receptors or through another mechanism. Additional recommendations have been proposed for future first-in-human studies to maximize subject safety. However, one must also accept the basic premise that, in general, first-in-human phase 1 studies are remarkably safe, and these rare events are not 100% avoidable during the drug development process.

Alpha-1-acid glycoprotein as an independent predictor for treatment effects and a prognostic factor of survival in patients with non-small cell lung cancer treated with docetaxel.

PURPOSE: To identify predictors of treatment outcome and survival in patients with non-small cell lung cancer (NSCLC) treated with docetaxel. EXPERIMENTAL DESIGN: The data were collected from 180 NSCLC patients enrolled in six docetaxel Phase II studies at a dose of 100 mg/m(2). Clinical end points for this study were safety reported as the first course adverse events requiring dose reduction, and efficacy was measured by response rate and survival. The independent variables included docetaxel dose, individual estimates of clearance, area under the plasma concentration time curve, extent of previous treatment, and covariables related to the patient's demographics, extent of disease, and performance status. The data were analyzed using a logistic regression model for response and severe adverse events and a Cox multivariate regression model for survival. RESULTS: Docetaxel exposure as measured by the area under the plasma concentration time curve was the only significant predictor (P < 0.0001) of severe toxicity during the first course of therapy. Baseline alpha1-acid glycoprotein (AAG) was the only significant predictor of response with an odds ratio of 0.44 for changes in AAG from 1.11 to 1.85 grams/liter (P = 0.0039). Cumulative dose, AAG, and extent of disease were independent predictors of survival (P < 0.005). The median survival varied from 15.6 months for patients with a low AAG (AAG < or = 1.11 grams/liter) to 5.5 months for patients with a high AAG (AAG >/= 1.85 grams/liter). CONCLUSION: AAG appears to be an independent predictor of response and a major objective prognostic factor of survival in patients with NSCLC treated with docetaxel chemotherapy.

Myocet (liposome-encapsulated doxorubicin citrate): a new approach in breast cancer therapy.

Doxorubicin, either as a single agent or in combination regimens, is considered to be one of the most active chemotherapeutic agents in the treatment of metastatic breast cancer. However, its clinical utility is limited by a cumulative, dose-dependent cardiac myopathy that can lead to potentially fatal congestive heart failure. Considerable research has gone into improving the therapeutic index of doxorubicin-based regimens. A new liposomal formulation of doxorubicin (Myocet, Elan Pharmaceuticals) has a significantly improved therapeutic index compared with conventional doxorubicin. The development of Myocet, a less cardiotoxic, better tolerated and equally efficacious doxorubicin, extends the therapeutic options in the overall management of breast cancer.

Istradefylline for Parkinson's disease patients experiencing motor fluctuations: results of the KW-6002-US-018 study.

BACKGROUND: Istradefylline (KW-6002) is a selective adenosine A(2A) receptor antagonist investigated as adjunctive therapy to levodopa in PD patients with motor response complications. In Phase 2b/3 studies, Istradefylline reduced OFF time without worsening troublesome dyskinesia and was well tolerated. METHODS: A randomized, 12-week, double-blind, placebo-controlled parallel-group study evaluated the efficacy of 10, 20, and 40 mg/day of Istradefylline in patients on levodopa therapy with motor response complications. The primary outcome measure was change from baseline to endpoint in the percentage of awake time/day spent in the OFF state as determined by patient diary. RESULTS: Six hundred and ten patients were randomized. Five hundred and eighty four patients were included in the Intent-to-treat (ITT) group-146 placebo patients and 149 in the 10 mg, 144 in the 20, and 145 patients in the 40 mg Istradefylline groups. Baseline demographics were similar between groups. Treatment cohorts had been diagnosed an average of 9 years diagnosis and 3.6 years from the onset of motor fluctuations; at baseline they had an average of 6.7 h of OFF time and an average UPDRS motor score of 22 when ON. At endpoint, the amount and percentage of OFF time did not differ between Istradefylline and placebo, however a dose-ordering response was observed. Changes from baseline in the UPDRS motor score in the on state for the 40 mg were modest but significant compared to placebo (2.9 vs. 0.8; p < 0.05). CONCLUSIONS: Although Istradefylline did not impact OFF time duration, it significantly improved motor score at 40 mg/day.

Population pharmacokinetic-pharmacodynamic analysis of istradefylline in patients with Parkinson disease.

This model-based analysis quantifies the population pharmacokinetic-pharmacodynamic efficacy and safety/tolerability relationships of orally administered istradefylline, a selective adenosine A(2A) receptor antagonist, in healthy participants and patients with Parkinson disease. Data from 6 phase 2/3 clinical trials comprised the population database, with 1760 and 1798 patients contributing to the efficacy and safety/tolerability analyses, respectively. The relationship between istradefylline area under the curve at steady state and percentage OFF time was described by a nonlinear model (Emax) based on time for the disease progression/placebo response component and an Emax model for the effect of istradefylline. The typical maximum decrease in percentage OFF time due to istradefylline exposure would be 5.79% (95% confidence interval = 4.09%-7.49%) with one-half of the maximum effect reached at an exposure of 1690 ng × hr/mL (95% confidence interval = 199-3180 ng × hr/mL). The pharmacokinetic-pharmacodynamic relationships for dyskinesia and dizziness were described by an Emax model, and for nausea, a power model was used. The probabilities of dyskinesia and dizziness are expected to plateau at a dose of 40 mg/d, and the probability of nausea is expected to continually rise as the dose is increased. Collectively, these results support a starting istradefylline dose of 20 to 40 mg/d.

Population pharmacokinetic analysis of istradefylline in healthy subjects and in patients with Parkinson's disease.

This model-based analysis quantifies the population pharmacokinetics (PK) of orally administered istradefylline, a selective adenosine A(2A) receptor antagonist, in healthy subjects and patients with Parkinson's disease, including the estimation of covariate effects on istradefylline PK parameters. Istradefylline plasma concentration data from 8 phase 1 and 8 phase 2/3 studies conducted in 1449 patients and normal, healthy volunteers aged from 18 to 87 years were best described by a 2-compartment model with first-order absorption parameterized in terms of apparent oral clearance (CL/F), apparent central volume of distribution (V2/F), apparent intercompartmental clearance (Q/F), apparent peripheral volume of distribution (V3/F) and a first-order absorption rate-constant (Ka). The typical population PK parameters were CL/F (5.76 L/h), V2/F (198 L), Q (21.6 L/h), V3/F (307 L), and Ka (0.464 h(-1)) for a 70-kg, nonsmoking Caucasian who had 55.6 kg of lean body mass, no presence of CYP3A4 inhibitors, and unknown food status. Smoking and CYP3A4 inhibitors as concomitant medications were important predictors of istradefylline exposure. Istradefylline area under the concentration-time curve at steady-state increased 35% (95% confidence interval, 18%-55%) in the presence of CYP3A4 inhibitors and decreased 38% (95% confidence interval, 26%-50%) in smokers. The population PK model described the observed concentration data well and was deemed appropriate for further evaluation of the istradefylline exposure-response relationship in patients with Parkinson's disease.

The use of putative placebo in active control trials: two applications in a regulatory setting.

For life-threatening diseases, ethical considerations preclude the inclusion of an untreated control group in the investigation of a new therapeutic agent when a standard therapy exists. In these cases, active controlled studies are conducted, and may be planned to demonstrate either superiority or equivalence/non-inferiority of the new drug over the standard therapy (active control). In the non-inferiority study, an important aspect is the ability to detect an inferior drug (assay sensitivity). It has been suggested that assay sensitivity for a non-inferiority study should be deduced from historical data, specifically placebo controlled studies with the standard therapy. The assessment of assay sensitivity may also be important in a superiority trial that fails to demonstrate a statistically significant difference between treatments, and the sponsor attempts to determine whether there is lack of inferiority as an alternative hypothesis for regulatory approval. This paper describes two methods of putative placebo analysis for assessing assay sensitivity in active controlled trials. One approach imputes a point estimate for the odds ratio (95 per cent confidence interval) for a new drug (T) compared to a placebo control (P). A Bayesian approach calculates the posterior probability that T is superior to P, or, that T is at least k per cent as good as the active control (A) and A is more effective than P. These methods are applied in two clinical/regulatory settings: a phase III trial comparing docetaxel (Taxotere) to doxorubicin in metastatic breast cancer patients, and a phase III programme with two trials comparing enoxaparin (Lovenox) plus aspirin to unfractionated heparin plus aspirin in patients with unstable angina or non-Q-wave myocardial infarction. The methodologies presented in this paper were used in securing regulatory approval for docetaxel in the treatment of locally advanced or metastatic breast cancer after failure of prior chemotherapy, and for enoxaparin in the treatment of acute coronary syndrome.

Pharmacokinetics of doxorubicin administered i.v. as Myocet (TLC D-99; liposome-encapsulated doxorubicin citrate) compared with conventional doxorubicin when given in combination with cyclophosphamide in patients with metastatic breast cancer.

Myocet (TLC D-99) is a liposomal formulation of the anti-neoplastic drug doxorubicin with an improved therapeutic index compared with conventional doxorubicin. The objective of this study was to assess the plasma disposition of doxorubicin when administered i.v. as TLC D-99 and to compare this to conventional drug. Metabolite (doxorubicinol) plasma levels were also quantitated in both treatment groups. Plasma was collected during the first course of treatment from 10 patients receiving TLC D-99 60 mg/m and 10 receiving conventional doxorubicin 60 mg/m2, each with cyclophosphamide 600 mg/m2. Samples were assayed for total doxorubicin (all doxorubicin regardless of whether it is encapsulated or not), encapsulated doxorubicin (TLC D-99 group only) and doxorubicinol using high-performance liquid chromatography. Plasma concentrations of total doxorubicin were higher in patients receiving TLC D-99 than in patients receiving conventional doxorubicin. The clearance of total doxorubicin after administration of TLC D-99 was lower (approximately 9-fold) and the volume of distribution at steady state was less (25-fold) than that of doxorubicin after conventional drug. Doxorubicinol was detected in the plasma of all patients in both treatment groups. The mean AUC(0-infinity) of doxorubicinol for patients receiving TLC D-99 (1.5+/-0.4 M x h) was not statistically different than that in patients receiving conventional doxorubicin (1.8+/-0.4 M x h), although the appearance of the peak doxorubicinol concentration occurred later and was lower in patients receiving TLC D-99. There was a correlation between the plasma AUC(0-infinity) of total doxorubicin and the degree of myelosuppression in patients receiving conventional doxorubicin, but this correlation was not found in patients receiving TLC D-99.