A new species of alkali-sink Paruroctonus Werner, 1934 (Scorpiones, Vaejovidae) from California's San Joaquin Valley.

Herein a new species of Paruroctonus Werner, 1934 is described from alkali-sink habitats in the San Joaquin Desert of central California, Paruroctonustularesp. nov. It can be differentiated from other Paruroctonus by a combination of morphological features including scalloped pedipalp fingers in males, specific setal counts and morphometric ratios, and specific patterns of fuscous pigmentation. It also inhabits a unique distribution allopatric with all other Paruroctonus species except P.variabilis Hjelle, 1982. Photographs of a large series of live P.tularesp. nov. from across their range and detailed images of several morphological features are provided, their distribution is modeled, a haplotype network is presented, and details about their habitat, ecology, and conservation are discussed.

Two new alkali-sink specialist species of Paruroctonus Werner 1934 (Scorpiones, Vaejovidae) from central California.

Herein we describe two new species of Paruroctonus (Werner 1934) from California: Paruroctonussoda sp. nov. from the Soda Lake playa at the center of the Carrizo Plain in San Luis Obispo county and Paruroctonusconclusus sp. nov. from the Koehn Lake playa in the Mojave Desert of Kern County. They can be differentiated from other Paruroctonus by a combination of morphological features including deeply scalloped pedipalp fingers in males, specific patterns of fuscous pigmentation, unique setal counts, and unique morphometric ratios. They can also be separated from one another by the latter three characters. Photographs of a large selection of live scorpions are provided, including detailed images and figures of many morphological features. Their distributions, habitats, and ecologies are discussed; and important steps towards their conservation are described.

Effect of Itraconazole, a Potent CYP3A4 Inhibitor, on the Steady-State Pharmacokinetics of Vemurafenib in Patients With BRAFV600 Mutation-Positive Malignancies.

The effects of itraconazole, a strong CYP3A4 inhibitor, on the steady-state pharmacokinetics of vemurafenib were evaluated in a phase 1, multicenter, open-label, fixed-sequence study. Patients with BRAFV600 mutation-positive metastatic malignancies received oral vemurafenib 960 mg twice daily on days 1 to 20 (period A) and oral vemurafenib 960 mg twice daily with oral itraconazole 200 mg once daily on days 21 to 40 (period B). A mixed-effects analysis of variance model was used to compare log-transformed area under the concentration-time curve during the dosing interval and maximum plasma concentration values for vemurafenib in 8 patients between period B (vemurafenib plus itraconazole) and period A (vemurafenib alone). Multiple doses of itraconazole increased steady-state exposure of vemurafenib by approximately 40%, with geometric least squares mean ratios (period B/period A) of 140% (90% confidence interval, 121-161) for both maximum plasma concentration and area under the concentration-time curve during the dosing interval. There was no apparent increase in incidence or severity of adverse events during coadministration of vemurafenib with itraconazole. In conclusion, coadministration of itraconazole with vemurafenib resulted in a modest increase in exposure of vemurafenib at steady state and was generally well tolerated.

Effect of Vemurafenib on the Pharmacokinetics of a Single Dose of Tizanidine (a CYP1A2 Substrate) in Patients With BRAFV600 Mutation-Positive Malignancies.

This phase 1 open-label, multicenter, 3-period, fixed-sequence study evaluated the effect of multiple doses of vemurafenib on the pharmacokinetics of 1 dose of tizanidine, a probe CYP1A2 substrate, in patients with BRAFV600 mutation-positive metastatic malignancy. Patients received 1 dose of tizanidine 2 mg on day 1 (period A), vemurafenib 960 mg twice daily on days 2-21 (period B), and 1 dose of tizanidine 2 mg and vemurafenib 960 mg twice daily on day 22 (period C). Log-transformed area under the concentration-time curve (AUC) and maximum plasma concentration (Cmax ) values for tizanidine in 16 patients were compared between periods A (tizanidine alone) and C (tizanidine plus vemurafenib) using an analysis of variance model. Multiple doses of vemurafenib increased plasma exposure of 1 dose of tizanidine, with geometric mean ratios (period C/period A) for Cmax , AUCinf , and AUClast of 2.15 (90%CI, 1.71-2.71), 4.22 (90%CI, 3.37-5.28), and 4.74 (90%CI, 3.55-6.33), respectively; 90%CIs were all outside predefined limits for lack of drug-drug interaction (0.82-1.22). This study confirmed vemurafenib as a moderate inhibitor of CYP1A2 in vivo, with a statistically significant drug-drug interaction with tizanidine. Caution should be exercised when dosing vemurafenib concurrently with CYP1A2 substrates.

Absolute Bioavailability of Vemurafenib in Patients With BRAFV600 Mutation-Positive Malignancies.

Vemurafenib is a BRAF kinase inhibitor indicated for the treatment of patients with BRAFV600 mutation-positive unresectable or metastatic melanoma and Erdheim-Chester disease. This phase 1, open-label, single-arm study was designed to estimate absolute bioavailability of oral vemurafenib at steady state and to characterize the pharmacokinetics of a single intravenous microdose of 14 C-labeled vemurafenib in patients with BRAFV600 mutation-positive malignancies. Patients received oral vemurafenib 960 mg twice daily on days 1 through 28, with a single intravenous infusion of 14 C-labeled vemurafenib solution (3 mL, corresponding to a radioactive dose of 18.5 kBq and a vemurafenib dose of 20 µg) given on the morning of day 21, immediately following the morning dose of oral vemurafenib. A total of 6 patients were enrolled. Four patients who received 14 C-labeled vemurafenib infusion were included in the pharmacokinetic and bioavailability analyses. Geometric mean absolute bioavailability of oral vemurafenib at steady state, calculated as the ratio of dose-normalized area under the curve during the dosing interval (AUCτ ) following oral vemurafenib dose to dose-normalized AUC from time 0 extrapolated to infinity (AUC0-inf ) following vemurafenib intravenous dose, was 57.8%. The majority of radioactivity (geometric mean 41%) was recovered in feces, and a small proportion (geometric mean 1.4%) was recovered in urine. Treatment-emergent adverse events occurred in 5 of 6 (83%) patients and were all grade 1/2 in severity, except for 1 grade-4 anaphylactic reaction occurring during infusion of 14 C-labeled vemurafenib, which was thought to be related to the excipient polysorbate 80 in the intravenous formulation.

Effect of Rifampicin on the Pharmacokinetics of a Single Dose of Vemurafenib in Patients With BRAFV600 Mutation-Positive Metastatic Malignancy.

Vemurafenib prolongs survival in patients with BRAFV600 -mutated advanced melanoma. In vitro studies show cytochrome P450 (CYP) 3A4 is involved in vemurafenib metabolism, but the effect of strong inducers or inhibitors of CYP3A4 on vemurafenib exposure in vivo is unknown. This phase 1, open-label, multicenter study evaluated the effect of rifampicin, a CYP3A4 inducer, on the pharmacokinetics of single-dose vemurafenib in 27 patients with BRAFV600 mutation-positive metastatic malignancy. Patients received a single oral dose of vemurafenib 960 mg on day 1, oral rifampicin 600 mg daily on days 8-16 (period B), and a single oral dose of vemurafenib 960 mg on day 17 and rifampicin 600 mg daily for days 17-23 (period C), with plasma samples obtained up to 168 hours after vemurafenib dosing. The geometric mean ratio (period C/period A) of area under the concentration-time curve from time zero to last measurable concentration time point and area under the concentration-time curve from time zero to infinity for vemurafenib (n = 23 for the pharmacokinetic analysis) was 0.61 (90% confidence interval, 0.48-0.78) and 0.60 (90% confidence interval, 0.47-0.76), respectively, indicating rifampicin significantly decreased vemurafenib plasma exposure by approximately 40%. The geometric mean ratio of the maximum concentration for vemurafenib was 1.1; this slight increase is likely owing to one outlier in period C. Adverse events were consistent with those previously seen for rifampicin and for vemurafenib monotherapy. Caution is advised when dosing vemurafenib concurrently with CYP3A4 inducers.

Effect of Vemurafenib on the Pharmacokinetics of a Single Dose of Digoxin in Patients With BRAFV600 Mutation-Positive Metastatic Malignancy.

The primary objective of this phase 1, open-label, multicenter, 3-period, fixed-sequence study was to evaluate the effect of multiple doses of vemurafenib on the pharmacokinetics of a single dose of digoxin, a probe P-glycoprotein (P-gp) substrate, in patients with BRAFV600 mutation-positive metastatic malignancy. Following a 28-day screening period, patients received a single oral dose of digoxin 0.25 mg on day 1 in period A, oral vemurafenib 960 mg twice daily for 21 days in period B (days 8-28), and a single oral dose of digoxin 0.25 mg on day 29 and vemurafenib 960 mg twice a day for 7 days (days 29-35) in period C. Log-transformed area under the concentration-time curve and peak concentration values for digoxin were compared between periods A (digoxin alone) and C (digoxin + vemurafenib) using an analysis of variance model. Twenty-six patients were evaluated for the primary pharmacokinetic analysis. The geometric mean ratio (period C/period A) of area under the curve to the last measurable concentration for digoxin was 1.82 (90%CI 1.63 to 2.02), and the geometric mean ratio of peak concentrations was 1.47 (90%CI 1.30 to 1.65); the 90%CIs were outside of the equivalence limits of 0.82 to 1.22, indicating an effect of vemurafenib on digoxin. Multiple oral doses of vemurafenib were generally well tolerated, with an adverse event profile similar to that previously seen in phase 2 and 3 studies of vemurafenib monotherapy. This study confirmed vemurafenib as an inhibitor of P-gp in vivo with a statistically significant drug-drug interaction with digoxin. Caution should be exercised when dosing vemurafenib concurrently with P-gp substrates.