Purpose: To identify the dose-limiting toxicity (DLT) and maximum tolerated dose (MTD) of the first-inclass, oral CDK4/6 inhibitor PD 0332991 administered once daily for 21 of 28 days (3/1 schedule) in patients with retinoblastoma protein (Rb)-positive advanced solid tumors and to describe pharmacokinetic-pharmacodynamic relationships relative to drug effects.Experimental Design: This open-label phase I study (NCT00141297) enrolled patients who received PD 0332991 orally in six dose-escalation cohorts in a standard 3 þ 3 design.Results: Forty-one patients were enrolled. DLTs were observed in five patients (12%) overall; at the 75, 125, and 150 mg once daily dose levels. The MTD and recommended phase II dose of PD 0332991 was 125 mg once daily. Neutropenia was the only dose-limiting effect. After cycle 1, grade 3 neutropenia, anemia, and leukopenia occurred in five (12%), three (7%), and one (2%) patient(s), respectively. The most common non-hematologic adverse events included fatigue, nausea, and diarrhea. Thirty-seven patients were evaluable for tumor response; 10 (27%) had stable disease for !4 cycles of whom six derived prolonged benefit (!10 cycles). PD 0332991 was slowly absorbed (median T max , 5.5 hours), and slowly eliminated (mean half-life was 25.9 hours) with a large volume of distribution (mean, 2,793 L). The area under the concentration-time curve increased linearly with dose. Using an E max model, neutropenia was shown to be proportional to exposure.Conclusions: PD 0332991 warrants phase II testing at 125 mg once daily, at which dose neutropenia was the sole significant toxicity. Clin Cancer Res; 18(2); 568-76. Ó2011 AACR.

The pharmacokinetics, safety, and tolerability of posaconazole, an investigational triazole antifungal, were evaluated following the administration of rising single and multiple oral doses. A total of 103 healthy adults were enrolled in two phase I trials. Each study had a double-blind, placebo-controlled, parallel-group design with a rising single-dose (RSD) or rising multiple-dose (RMD) scheme. In the RSD study, subjects received single doses of posaconazole oral tablets (50 to 1,200 mg) or placebo. In the RMD study, subjects received posaconazole oral tablets (50 to 400 mg) or placebo twice daily for 14 days. By using model-independent methods, the area under the plasma concentration-time curve and the maximum concentration in plasma were determined and used to assess dose proportionality. In the RSD study, the levels of posaconazole in plasma increased proportionally between the 50-and 800-mg dose range, with saturation of absorption occurring above 800 mg. Dose proportionality was also observed in the RMD study. In both studies, the apparent volume of distribution was large (range, 343 to 1,341 liters) and the terminal-phase half-life was long (range, 25 to 31 h). Posaconazole was well tolerated at all dose levels, and the adverse events were not dose dependent. No clinically significant changes in clinical laboratory test values or electrocardiograms were observed. Following the administration of single and twice-daily rising doses, the level of posaconazole exposure increased in a dose-proportional manner. The long elimination-phase half-life of posaconazole supports once-or twice-daily dosing in clinical trials; however, additional studies are required to determine if further division of the dose will enhance exposure.The evolution of oral triazole antifungal agents began in the 1980s with the introduction of fluconazole and itraconazole for the treatment of systemic fungal infections. In recent years, the patterns of Candida infections have changed. Previously, Candida albicans was the most prevalent cause of Candida infections, whereas in recent times, other Candida species, such as C. glabrata and C. krusei, have become common infectioncausing pathogens (6). In addition to this shift in species, fluconazole-and itraconazole-resistant Candida strains have emerged, prompting clinicians to search for alternative treatment options. The emergence of new fungal diseases caused by fungi that were previously not thought to be pathogenic has also limited the usefulness of older triazole compounds for the treatment of invasive infections, especially in immunocompromised patients. For example, fusariosis and zygomycosis are increasingly common; however, the treatments for these infections are limited (23). In light of the need for more potent and broad-spectrum therapeutic options, posaconazole (SCH 56592), a novel oral triazole derivative structurally similar to itraconazole (Fig. 1), is in development for the treatment of invasive fungal infections.Posaconazole has enhanced activity against many old, new, and ...

AimsThis randomized, crossover, single-dose study evaluated the relative oral bioavailability of posaconazole suspension and coprecipitate tablet formulations. Additionally, the study determined whether systemic exposure to posaconazole was affected by prandial status or by the fat content of a meal. MethodsThis was a randomized, open-label, four-way crossover, single-dose study in 20 healthy men. Posaconazole pharmacokinetics were evaluated over 72 h following a single oral dose of posaconazole suspension (200 mg/5 ml) administered with a high-fat meal, a nonfat breakfast, or after a 10 h fast, or posaconazole tablets (2 ¥ 100 mg) administered with a high-fat meal. ResultsThe posaconazole suspension showed a significant increase in bioavailability compared with the tablet (increase in AUC(0,72 h) = 137% (90% confidence interval (CI) 119%, 156% and C max = 123% (90% CI 104%, 146%). The mean increases in AUC(0,72 h) and C max values were about 400% when administered with a high-fat meal compared with administration of the suspension in the fasting state (AUC(0,72 h) 90% CI 343%, 448%; C max 90% CI 352%, 493%). Administration of the suspension with a nonfat meal enhanced exposure, resulting in an increase in AUC(0,72 h) of 264% (90% CI 231%, 302%) and in C max of 296% (90% CI 250%, 350%) relative to the fasted state. ConclusionsThe suspension formulation of posaconazole was associated with enhanced systemic exposure and increased relative bioavailability compared with the tablet. Food substantially enhanced the rate and extent of posaconazole absorption in healthy subjects.

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