Guaifenesin Pharmacokinetics Following Single-Dose Oral Administration in Children Aged 2 to 17 Years.

This study characterized guaifenesin pharmacokinetics in children aged 2 to 17 years (n = 40) who received a single oral dose of guaifenesin (age-based doses of 100-400 mg) 2 hours after breakfast. Plasma samples were obtained before and for 8 hours after dosing and analyzed for guaifenesin using liquid chromatography-tandem mass spectrometry. Pharmacokinetic parameters were estimated using noncompartmental methods, relationships with age were assessed using linear regression, and dose proportionality was assessed on 95% confidence intervals. Based on the upper dose recommended in the monograph (for both children and adolescents), area under the curve from time zero to infinity and maximum plasma concentration both increased with age. However, when comparing the upper dose for children aged 2 to 11 years with the lower dose for adolescents aged 12 to 17 years, similar systemic exposure was observed. As expected due to increasing body size, oral clearance (CLo ) and terminal volume of distribution (Vz /F) increased with age. Due to a larger increase in Vz /F than CLo , an increase in terminal exponential half-life was also observed. Allometric scaling indicated no maturation-related changes in CLo and Vz /F.

Metabolism and disposition of dasatinib after oral administration to humans.

SPRYCEL (dasatinib, BMS-354825; Bristol-Myers Squibb, Princeton, NJ), a multiple kinase inhibitor, is currently approved to treat chronic myelogenous leukemia and Philadelphia chromosome-positive acute lymphoblastic leukemia tumors in patients who are resistant or intolerant to imatinib mesylate (Gleevec; Novartis, Basel, Switzerland). After a 100-mg single p.o. dose of [(14)C]dasatinib to healthy volunteers, the radioactivity was rapidly absorbed (T(max) approximately 0.5 h). Both dasatinib and total radioactivity (TRA) plasma concentrations decreased rapidly with elimination half-life values of <4 h. Dasatinib was the major drug-related component in human plasma. At 2 h, dasatinib accounted for 25% of the TRA in plasma, suggesting that metabolites contributed significantly to the total drug-related component. There were many circulating metabolites detected that included hydroxylated metabolites (M20 and M24), an N-dealkylated metabolite (M4), an N-oxide (M5), an acid metabolite (M6), glucuronide conjugates (M8a,b), and products of further metabolism of these primary metabolites. Most of the administered radioactivity was eliminated in the feces (85%). Urine recovery accounted for <4% of the dose. Dasatinib accounted for <1 and 19% of the dose in urine and feces, respectively, suggesting that dasatinib was well absorbed after p.o. administration and extensively metabolized before being eliminated from the body. The exposures of pharmacologically active metabolites M4, M5, M6, M20, and M24 in patients, along with their cell-based IC(50) for Src and Bcr-Abl kinase inhibition, suggested that these metabolites were not expected to contribute significantly toward in vivo activity.

Phase 2 study of cetuximab in patients with advanced hepatocellular carcinoma.

BACKGROUND: Epidermal growth factor receptor (EGFR) and ligand expression is frequently seen in hepatocellular carcinoma (HCC). A phase 2 study was performed with cetuximab, a chimeric monoclonal antibody that binds specifically to EGFR, in patients with advanced HCC. METHODS: Eligibility criteria included unresectable or metastatic measurable HCC, an Eastern Cooperative Oncology Group performance status

Single-patient drug trial methodology for allergic rhinitis.

BACKGROUND: Historically, single-patient trials (SPTs) have been specifically designed for each patient, requiring significant time and effort for execution. There has been no previous attempt to standardize an SPT for routine commercial availability. OBJECTIVE: To validate the use of an SPT method to discriminate effectiveness and adverse events while comparing drugs/doses in patients with allergic rhinitis. DESIGN: Double-blind, randomized, 4 paired-period, multiple-crossover SPT. SETTING: Academic and commercial investigative sites. PATIENTS: Thirty-six patients with allergic rhinitis were evaluated for the most appropriate treatment; 6 of these participated in 2 different SPTs. INTERVENTIONS: Treatment of symptoms of allergic rhinitis by comparing either loratadine with chlorpheniramine maleate or loratadine with placebo in a series of SPTs. MEASUREMENTS: Effectiveness endpoints were selected from a modern, Food and Drug Administration (FDA)-approved new drug application. Expected adverse events were directly solicited; unsolicited events were also recorded. Total signs and symptoms cumulatively included sneezing, runny nose, itchy nose, teary eyes, and itchy eyes. Quality of life was measured by the most bothersome symptom and the patient's global evaluation. RESULTS: Of 42 initiated SPTs, 40 (95%) provided complete data and 1 (2%) provided partial data, resulting in 41 (98%) evaluable tests. Thirty-one evaluable SPTs compared loratadine 10 mg/d with chlorpheniramine maleate 12 mg twice daily, and 10 SPTs compared loratadine 10 mg/d with placebo. Four of 31 SPTs (13%) showed significant superiority for loratadine over chlorpheniramine maleate and 5 of 31 (16%) for chlorpheniramine maleate over loratadine. Twenty-two of 31 (71%) showed parity performance between loratadine and chlorpheniramine maleate. Loratadine was significantly superior to placebo in 3 of 10 trials (30%), consistent with rates found in 3 pivotal group trials used for FDA approval (24%, 17%, and 0%). Sleepiness could be discriminated for loratadine versus placebo and for chlorpheniramine maleate versus loratadine. CONCLUSIONS: The allergic rhinitis SPT proved to be acceptable to patients, feasible to administer, and reproducible. It can statistically discriminate effectiveness and adverse events, serving as a useful, prognostic tool in community practice.

Validation of a single-patient drug trial methodology for personalized management of gastroesophageal reflux disease.

BACKGROUND: Single-patient trials (SPTs) are randomized, often multiple-crossover trials where patients serve as their own control to determine their appropriate treatment. Historically, SPTs have been individually customized, requiring significant time and cost for execution. The patient.s progress is tracked and evaluated in a blinded, multiple-crossover design comparing different therapies. Standardized, cost-efficient SPTs could help avoid (a) inappropriate extrapolation of the average-group outcomes from parallel, clinical trials to community-practice patients and (b) wasteful prescribing of high-cost drugs. Aggregate SPT results can also provide new data on appropriate drug prescribing in subpopulations. OBJECTIVE: To validate a standardized, commercially useful SPT method for comparing drugs/doses in patients with gastroesophageal reflux disease (GERD) requiring maintenance therapy. METHODS: A double-blind, single-dummy, randomized, 3 paired-period (28 days per period, 14 days per leg), multiple-crossover, SPT comparing omeprazole 20 mg daily and ranitidine hydrochloride (ranitidine) 150 mg twice daily was employed for 32 patients with GERD taking acid-suppressing medications chronically. Endpoints to determine effectiveness were selected from a recently approved new-drug application. Heartburn, regurgitation, difficulty swallowing, epigastric pain, and nausea were evaluated daily. Use of rescue medications was also measured. Quality of life was measured weekly by the patient.s global evaluation. Observations for days 1 to 4 were excluded by using aggregate database sensitivity analyses to define appropriate surrogate washout periods. Frequently reported adverse events found in labeling for acid-suppressing drugs were directly solicited and compared between treatments. Unsolicited events were recorded. Patients completed a test-kit-acceptability questionnaire. RESULTS: Fourteen of 27 evaluable SPTs (52%) showed significant superiority for omeprazole over ranitidine and 7 of 27 (26%) for ranitidine over omeprazole. Four of 27 (15%) showed parity performance. Neither agent could be recommended in 2 of 27 (7%) of SPTs due to significant adverse events experienced with both drugs. For those patients taking proton pump inhibitors (PPIs) prior to enrollment, the estimated step-down substitution rate from omeprazole to ranitidine, combined with the drug therapy discontinuation rate, was 40% (90% confidence interval: 22% to 68%). The majority of patients rated the test kits as appropriate and desirable. CONCLUSION: Omeprazole was the appropriate treatment in only 52% of these chronic users of acid-suppressing drugs. Eleven of 27 trials (41%) indicated that ranitidine was the preferred treatment. The SPT method proved acceptable to patients, feasible to administer, and reproducible. It can statistically discriminate effectiveness and adverse events and serve as a useful, prognostic tool in community practice by determining the least costly, evidence-based, appropriate treatment.