Caspofungin exposure-response relationships in adult patients with mucosal or invasive candidiasis.

Caspofungin is an echinocandin antifungal agent administered once daily as an intravenous infusion. Relationships between caspofungin exposure and clinical efficacy and safety were investigated. End-of-infusion (CEOI ) and trough (C24 hours ) concentrations were obtained in 218 patients with mucosal (i.e., esophageal and/or oropharyngeal) candidiasis (MC) receiving caspofungin 35, 50, or 70 mg/day and 278 patients with invasive candidiasis (IC) receiving 50, 100, or 150 mg/day. Area under the plasma concentration-time curve (AUC0-24 hours ) was obtained in a subset of MC patients (n = 99). Odds ratios were estimated for the association between log-transformed PK and efficacy response and the occurrence of common adverse events. No pharmacokinetic or hybrid parameter (ratio of AUC:MIC, CEOI :MIC, C24 hours :MIC) was significantly correlated with overall treatment outcome in either MC or IC, although this patient population may exhibit confounding factors which masked a potential pharmacokinetic/pharmacodynamic relationship. An exploratory evaluation of MC identified significant pharmacokinetic correlations with endoscopic response, but not symptom response. Statistically significant associations were identified for IC patients with C. parapsilosis infections. Occurrence of clinical adverse events and/or laboratory abnormalities did not appear to be increased by higher caspofungin plasma concentrations. Caspofungin concentrations achieved with 50 mg/day are generally within the therapeutic window for the treatment of candidiasis.

A semimechanistic model of the time-course of release of PTH into plasma following administration of the calcilytic JTT-305/MK-5442 in humans.

JTT-305/MK-5442 is a calcium-sensing receptor (CaSR) allosteric antagonist being investigated for the treatment of osteoporosis. JTT-305/MK-5442 binds to CaSRs, thus preventing receptor activation by Ca(2+) . In the parathyroid gland, this results in the release of parathyroid hormone (PTH). Sharp spikes in PTH secretion followed by rapid returns to baseline are associated with bone formation, whereas sustained elevation in PTH is associated with bone resorption. We have developed a semimechanistic, nonpopulation model of the time-course relationship between JTT-305/MK-5442 and whole plasma PTH concentrations to describe both the secretion of PTH and the kinetics of its return to baseline levels. We obtained mean concentration data for JTT-305/MK-5442 and whole PTH from a multiple dose study in U.S. postmenopausal women at doses of 5, 10, 15, and 20 mg. We hypothesized that PTH is released from two separate sources: a reservoir that is released rapidly (within minutes) in response to reduction in Ca(2+) binding, and a second source released more slowly following hours of reduced Ca(2+) binding. We modeled the release rates of these reservoirs as maximum pharmacologic effect (Emax ) functions of JTT-305/MK-5442 concentration. Our model describes both the dose-dependence of PTH time of occurrence for maximum drug concentration (Tmax ) and maximum concentration of drug (Cmax ), and the extent and duration of the observed nonmonotonic return of PTH to baseline levels following JTT-305/MK-5442 administration.

Safety and pharmacokinetics of higher doses of caspofungin in healthy adult participants.

Caspofungin was the first in a new class of antifungal agents (echinocandins) indicated for the treatment of primary and refractory fungal infections. Higher doses of caspofungin may provide another option for patients who have failed caspofungin or other antifungal therapy. This study evaluated the safety, tolerability, and pharmacokinetics of single 150- and 210-mg doses of caspofungin in 16 healthy participants and 100 mg/d for 21 days in 20 healthy participants. Other than infusion site reactions and 1 reversible elevation in alanine aminotransferase (≥2× and <4× upper limit of normal), caspofungin was generally well tolerated. Geometric mean AUC(0-∞) after single 150- and 210-mg doses was 279.7 and 374.9 µg·h/mL, respectively; peak concentrations were 29.4 and 33.5 µg/mL, respectively; and 24-hour postdose concentrations were 2.8 and 4.2 µg/mL, respectively. Steady state was achieved in the third week of dosing. Following multiple 100-mg doses of caspofungin, day 21 geometric mean AUC(0-24) was 227.4 µg·h/mL, peak concentration was 20.9 µg/mL, and trough concentration was 4.7 µg/mL. Beta-phase t(1/2) was ~8 to ~13 hours. Caspofungin pharmacokinetics at these higher doses were dose proportional to and consistent with those observed at lower doses, suggesting a modest nonlinearity of increased accumulation with dose, which was considered not clinically meaningful.

Pharmacokinetics and safety of twice-daily atazanavir 300 mg and raltegravir 400 mg in healthy individuals.

BACKGROUND: Atazanavir plus raltegravir 300/400 mg twice daily is being explored as a ritonavir- and nucleoside-sparing treatment strategy. The pharmacokinetics and safety of this combination in healthy individuals were evaluated. METHODS: A total of 22 healthy individuals received raltegravir 400 mg on days 1-5, atazanavir 300 mg on days 6-12 and atazanavir plus raltegravir 300/400 mg on days 13-26, twice daily with a light meal. Serial blood samples were collected 12 h after the morning dose on days 5, 12 and 26; safety assessments, clinical laboratory data and serial electrocardiograms (ECGs) at 0, 2 and 6 h were obtained. RESULTS: Raltegravir coadministration reduced atazanavir geometric mean maximum plasma concentration (C(max)), area under the plasma concentration-time curve from 0 to 12 h post-dose (AUC(0-12)) and trough plasma concentration (C(min)) by 11%, 17% and 29%, respectively, compared with atazanavir alone. Geometric mean atazanavir C(min) was 817 ng/ml (range 250-1,550) with raltegravir coadministration. Atazanavir increased raltegravir geometric mean C(max), AUC(0-12) and C(min) by 39%, 54% and 48%, respectively. All adverse events were of mild or moderate intensity. Hyperbilirubinaemia and ECG PR increases with atazanavir were similar to those of atazanavir/ritonavir once daily. No corrected QT prolongations were noted. Mean QRS increase from baseline was 11.0 ms (range 2-25) after receiving atazanavir for 7 days; no further QRS increase was noted and no QRS interval was >120 ms with raltegravir coadministration. No ECG changes were observed with raltegravir alone. CONCLUSIONS: Coadministration of atazanavir and raltegravir 300/400 mg twice daily decreased atazanavir AUC(0-12) and C(min) relative to atazanavir alone, and increased AUC(0-12) of raltegravir relative to raltegravir alone. Atazanavir and raltegravir alone and coadministered appeared safe and well-tolerated.

A single supratherapeutic dose of vorinostat does not prolong the QTc interval in patients with advanced cancer.

PURPOSE: This dedicated QTc phase I study, conducted in advanced-stage cancer patients, assessed the effect of a single supratherapeutic dose (800 mg) of vorinostat on the QTc interval. EXPERIMENTAL DESIGN: A randomized, partially blind, placebo-controlled, two-period, crossover study was conducted. Patients (n = 25) received single doses of 800 mg vorinostat and placebo in the fasted state. Holter electrocardiogram monitoring was done before each treatment and for 24 h postdose. Blood samples for vorinostat concentration were collected through 24 h postdose following vorinostat treatment only. Prescribed electrocardiogram and blood sampling times were designed to capture the expected C(max) of vorinostat. RESULTS: Twenty-four of the 25 patients enrolled in the study were included in the QTc analysis. The upper bound of the two-sided 90% confidence interval for the QTcF interval for the placebo-adjusted mean change from baseline of vorinostat was <10 ms at every time point. No patient had a QTcF change from baseline value >30 ms. One patient had QTcF values >450 ms (seen after both vorinostat and placebo administration) and none had values >480 ms. Mean AUC(0-infinity) and C(max) values attained were on the order of approximately 1.93- and approximately 1.41-fold higher, respectively, compared with the 400 mg clinical dose. Based on assessment of clinical and laboratory adverse experiences, single doses of 800 mg vorinostat were generally well tolerated. CONCLUSIONS: Administration of a single supratherapeutic dose of the histone deacetylase inhibitor vorinostat is not associated with prolongation of the QTc interval. A dedicated QTc study in advanced cancer patients is a robust means for assessing risk for ventricular repolarization prolongation.

Engineering RGD nanopatterned hydrogels to control preosteoblast behavior: a combined computational and experimental approach.

The adhesion ligand arginine-glycine-aspartic acid (RGD) has been coupled to various materials to be used as tissue culture matrices or cell transplantation vehicles, and recent studies indicate that nanopatterning RGD into high-density islands alters key cell behaviors. Previous studies have failed, however, to conclusively decouple the effects of RGD bulk density and individual pattern parameters (i.e. RGDs/island and island distribution) on these altered cell responses. Using a nanopatterned RGD-coupled alginate hydrogel matrix, this work combines computational, statistical and experimental approaches to elucidate the effects of RGD patterns on four key cell responses. This study shows that in MC3T3 preosteoblasts focal adhesion kinase (FAK) Y397 phosphorylation, cell spreading, and osteogenic differentiation can be controlled by RGD nanopatterning, with the distribution of islands throughout the hydrogel (i.e. how closely spaced the islands are) being the most significant pattern parameter. More closely spaced islands favor FAK Y397 phosphorylation and cell spreading, while more widely spaced islands favor differentiation. Proliferation, in contrast, is primarily a function of RGD bulk density. Nanopatterning of cell adhesion ligands has tremendous potential as a simple tool to gain significant control over multiple cell behaviors in engineered extracellular matrix (ECM).

Multi-scale modeling to predict ligand presentation within RGD nanopatterned hydrogels.

The adhesion ligand RGD has been coupled to various materials to be used as tissue culture matrices or cell transplantation vehicles, and recent studies indicate that nanopatterning RGD into high-density islands alters cell adhesion, proliferation, and differentiation. However, elucidating the impact of nanopattern parameters on cellular responses has been stymied by a lack of understanding of the actual ligand presentation within these systems. We have developed a multi-scale predictive modeling approach to characterize the adhesion ligand nanopatterns within an alginate hydrogel matrix. The models predict the distribution of ligand islands, the spacing between ligands within an island and the fraction of ligands accessible for cell binding. These model predictions can be used to select pattern parameter ranges for experiments on the effects of individual parameters on cellular responses. Additionally, our technique could also be applied to other polymer systems presenting peptides or other signaling molecules.

Nanoscale Adhesion Ligand Organization Regulates Osteoblast Proliferation and Differentiation.

It was hypothesized that nanoscale adhesion ligand spacing regulates cell adhesion, proliferation, and differentiation, and that this control can be decoupled from the overall ligand density. Alginate was chemically modified with a peptide containing the cell adhesion sequence arginine-glycine-aspartic acid (RGD), and the nanoscale spacing of RGD ligands in alginate gels was varied. A decrease in the RGD island spacing from 78 to 36 nm upregulated the proliferation rates of MC3T3-E1 cells from 0.59 ± 0.08 to 0.73 ± 0.03 day-1 and resulted in 4-fold increase of the osteocalcin secretion rate. This finding was independent of the bulk ligand density of gels. These results indicate that nanoscale ligand organization may provide an important variable to regulate cell functions in many biomedical applications, including tissue engineering.