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Levodopa (LD) combined with a peripheral inhibitor of aromatic L-amino acid decarboxylase, such as carbidopa (CD), continues to be the most effective treatment of Parkinson disease and is well tolerated at all stages of the disease.1–3 Immediate-release formulations of LD require frequent dosing because of the short half-life of LD and result in marked fluctuations in the LD plasma concentrations. The pulsatile LD profile results in fluctuations in the clinical response such as on-off and wearing off and may play an important role in LD-induced dyskinesia.4,5 Intravenous and intraduodenal infusion of LD provide more stable plasma concentrations and can result in a smoother clinical response in patients with motor fluctuations.6–8 However, intravenous infusion is not practical for long-term therapy, and duodenal infusion requires surgery and may only be appropriate for the most severe patients. An oral product that provides more consistent LD absorption and more stable plasma concentrations would address a major unmet clinical need to enhance efficacy and reduce or prevent motor oscillations and drug-induced dyskinesias.9 However, current sustained-release formulations of CD-LD and the addition of a cathechol-O-methyltransferase inhibitor (eg, entacapone) to immediate-release CD-LD have been of limited value.10,11 Controlled-release formulations have been associated with erratic absorption, variable plasma concentrations, and a delayed onset of effect.12,13 Carbidopa-LD products containing entacapone have been associated with a shorter time to onset of dyskinesia and increased frequency of dyskinesia compared with CD-LD products.14 IPX066 (RYTARY [CD and LD]; Impax Laboratories, Inc, Hayward, Calif) is an extended-release multiparticulate capsule formulation of CD-LD that has demonstrated efficacy in patients with early and advanced Parkinson disease.15,16 IPX066 capsules are available in a 1:4 ratio of CD:LD in 4 CD-LD dose strengths: 23.75–95, 36.25–145, 48.75–195, and 61.25–245 mg of CD-LD. Food has been reported to affect the absorption of various drugs and, in particular, affect the performance of LD formulations.17–19 Absorption of LD occurs mainly in the proximal third of the small intestine. Delayed gastrointestinal transit may affect CD-LD absorption. Gastric emptying is affected by the composition and physicochemical properties of a meal. In addition, LD and its derivative dopamine have also been reported to affect gastric emptying.20,21 The objectives for this investigation were to characterize the dose proportionality of the 4 dose strengths of IPX066 capsules and to compare the pharmacokinetics of 1 and 2 capsules of the highest strength (61.25-245 mg of CD-LD). In addition, the effect of a high-fat, high-calorie breakfast and the effect of sprinkling the capsule contents on applesauce on the pharmacokinetics of IPX066 were assessed.

During the past 2 decades, there have been advances in the definition, measurement, and application in clinical trials and practice of health-related quality of life (HRQOL). In addition, the importance of bringing the patient's voice to medical decision making has been increasing. However, there remains some question as to the importance of the HRQOL construct in cancer treatment. This article addresses several issues related to HRQOL in oncology including (1) reasons for including HRQOL measurements in treatment studies, (2) the importance of HRQOL information in the absence of clinical therapeutic benefit, (3) determining clinical significance of HRQOL data, and (4) when it may not be important to measure HRQOL. HRQOL information can be a useful outcome of therapeutic benefit for patients undergoing cancer treatments, especially when it is associated with a clinical intervention such as additional supportive services, symptom management, and a new medicine that reduces tumor size or extends life. Moreover, it is important to establish the meaningful important difference levels on HRQOL questionnaires to trigger health professionals to begin, maintain, or end cancer interventions.

The effect of ritonavir 400 mg/saquinavir 400 mg twice daily on the stereoselective pharmacokinetics of methadone was examined in 12 HIV-infected. methadone-using study subjects. Design: A 24-hour methadone pharmacokinetic study was performed before antiretroviral therapy was begun and after 15 days of therapy. Methadone concentration was measured by a chiral plasma assay because the drug is administered as a racemic mixture of R- and S-methadone, but only the R-isomer is active. Both changes in plasma protein binding and changes in objective and subjective opioid effect were monitored. Results: Ritonavir/saquinavir administration was associated with 40% decrease in total S-methadone AUC 0- 24hr and 32% decrease in R-methadone area under the curve (AUC) 0 0-24hr , and both changes were statistically significant (p =.001 for both).. When AUC was corrected for the changes in protein binding induced by ritonavir/saquinavir, R-methadone free AUC 0 24hr decreased 19.6% whereas the S-methadone decreased 24.6%, neither of these changes was statistically significant (p =.129 and p =.0537, respectively). This change in methadone exposure was not associated with any evidence of withdrawal from narcotics and no modification of methadone dose was required. Conclusions: Our data indicate that ritonavir/saquinavir administration is associated with induction of metabolism of methadone but this is greater for the inactive S-methadone. However, approximately 37% of the decrease in the total R-methadone exposure can be explained by protein binding displacement. Ritonavir/saquinavir can be used in HIV-infected people taking methadone without routine dose adjustments.

Objectives. Although the broad impacts of Alzheimer's disease (AD) are increasingly recognized, little work has focused on the overall health-related quality of life experienced by Alzheimer's disease patients and their caregivers. The study had two main objectives: (1) to test the feasibility of measuring health utilities in Alzheimer's disease with a generic preference-weighted instrument using proxy respondents and (2) to assess the utility scores of Alzheimer's disease patients (and their caregivers) in different disease stages and care setting. Methods. A cross-sectional study of 679 Alzheimer's disease patient/caregiver pairs was conducted at 13 sites in the United States: four academic medical centers, four managed care plans, two assisted living facilities, and three nursing homes. The Health Utilities Index Mark II (HUI:2) questionnaire was administered to caregivers of patients who responded both as proxies for patients and for themselves. Responses to the questionnaire were converted into a global utility score, between 0 and 1, using the HUI:2 multi-attribute utility function. Results. Global utility scores varied considerably across patients' Alzheimer's disease stage: for the six stages assessed (questionable, mild, moderate, severe, profound, and terminal), mean utility scores were 0.73, 0.69, 0.53, 0.38, 0.27, and 0.14, respectively. In multiple regression analyses, Alzheimer's disease stage was a negative and significant predictor of utility scores for patients; setting did not exert an independent effect. Utility scores for the caregivers were insensitive to patients' Alzheimer's disease stage and setting. Conclusions. Patients' Alzheimer's disease stage had a substantial influence on health utilities, as measured by the HUI:2. More research is needed to assess the validity of using proxy respondents.

The effect of coadministration of ritonavir and didanosine (ddI) on the pharmacokinetics of these drugs was investigated in a single-center, three-period, crossover study. Eighteen asymptomatic, HIV-positive men were assigned randomly to 6 different sequences of 3 regimens: ddI (200 mg every 12 hours) alone for 4 days, ritonavir (600 mg every 12 hours) alone for 4 days, and 4 days of ddI with ritonavir under dose-staggering conditions. Although not statistically significant, ritonavir concentrations were slightly higher on average (

The use of self-report questionnaires for the assessment of health-related quality of life (HRQOL) is increasingly common in clinical research. This method of data collection may be less suitable for patient groups who suffer from cognitive impairment, however, such as patients with brain cancer. In such cases, one can consider employing the patients' significant others as proxy raters of the patients' health-related quality of life. The authors examined the response agreement between patients with brain cancer and their significant others on a health-related quality of life instrument commonly used in cancer clinical trials, the EORTC QLQ-C30, and on a brain cancer-specific questionnaire module, the QLQ-BCM.The study sample consisted of 103 pairs of patients, with either recently diagnosed or recurrent brain cancer, and their significant others (75% spouses, 22% relatives, and 3% friends). Patients and proxies independently completed the EORTC QLQ-C30 and the QLQ-BCM at three different times.Approximately 60% of the patient and proxy scores were in exact agreement, with more than 90% of scores being within one response category of each other. For most HRQOL dimensions assessed, moderate to good agreement was found. Statistically significant differences in mean scores were noted for several dimensions, with proxies tending to rate the patients as having a lower quality of life than the patients themselves. With the exception of fatigue ratings, this response bias was of a limited magnitude. Less agreement and a more pronounced response bias was observed for the more impaired patients, and particularly for patients exhibiting mental confusion. This finding was confirmed by longitudinal analyses, which indicated lower levels of patient-proxy agreement at follow-up for those patients whose physical or neurologic condition had deteriorated over time.In general, patients and their significant others provide similar ratings of the patients' quality of life. Lower levels of agreement and more biased ratings can be expected among those patients for whom the need for proxies is most salient. It is argued, however, that discrepancies between patient-proxy ratings should not be interpreted, a priori, as evidence of the inaccuracy or biased nature of proxy-generated data. Future studies are needed to examine the relative validity and reliability of patient-versus proxy-generated health-related quality of life scores.

Objective: To compare efficacy and safety of IPX066 to CLE in advanced fluctuating PD subjects. Background IPX066 is designed to provide rapid absorption and maintain a longer duration of stable LD concentrations than Immediate-release CD-LD. Design/Methods: This is a randomized, double-blind, 2-period cross-over study in advanced subjects on stable CLE (N=110). After open-label dose conversion to IPX066 (6 weeks), subjects were randomized to receive IPX066 followed by CLE or vice versa (2 weeks/period with 1 week open-label IPX066 between periods). The primary efficacy endpoint was percent “off- time” during waking hours (24-hr subject diaries). Results: During double-blind cross-over period, IPX066 demonstrated lower percentage of “off-time” than CLE (23.98% vs. 32.48%, p p p Conclusions: IPX066, dosed 3.5 times/day, improved control of motor symptoms compared to CLE, dosed 5.0 times/day in PD patients with motor fluctuations. These results indicate IPX066 may be a useful treatment option in advanced PD patients. Supported by: IMPAX Pharmaceuticals, a division of Impax Laboratories, Inc., Hayward. Disclosure: Dr. Stocchi has received personal compensation for activities with TEVA, Novartis, GlaxoSmithKline, Lundbeck, Schering-Plough, IMPAX, Merck Serono, IMPAX and UCB. Dr. Stocchi has received research support from Novartis and GlaxoSmithKline. Dr. Dillmann has received personal compensation for activities with GSK and Orion. Dr. Ellenbogen has received personal compensation for activities with XenoPort, Inc., Teva Neuroscience, Boehringer Ingelheim Pharmaceuticals, Inc., Allergan, Inc., Novartis, Ipsen and GlaxoSmithKline, Inc. as a speaker and/or consultant. Dr. Hsu has received personal compensation for activities with IMPAX Labs as an employee.Dr. Hsu holds stock and/or stock options in IMPAX Labs, which sponsored research in which Dr.Hsu was involved as an investigator.Dr. Hsu holds stock and/or stock options in IMPAX Labs. Dr. Khanna has received personal compensation for activities with IMPAX Pharma as an employee. Dr. Khanna holds stock and/or stock options in IMPAX Pharma, which sponsored research in which Dr. Khanna was involved as an investigator. Dr. Rubens has received personal compensation for activities with IMPAX Pharmaceuticals as an employeeDr. Rubens holds stock and/or stock options in IMPAX Pharmaceuticals, which sponsored research in which Dr. Rubens was involved as an investigator. Dr. Liang has received personal compensation for activities with Boehringer Ingelheim, GlaxoSmithKline, Novartis, TEVA, and Chelsea. Dr. Gupta has received personal compensation for activities with Impax Labs as an employee. Dr. Gupta holds stock and/or stock options in Impax Labs, which sponsored research in which Dr. Gupta was involved as an investigator. Dr. Gupta has received research support from Impax Labs.