The metabolic response of the Bradypus sloth to temperature.

Poikilotherms and homeotherms have different, well-defined metabolic responses to ambient temperature (T a ), but both groups have high power costs at high temperatures. Sloths (Bradypus) are critically limited by rates of energy acquisition and it has previously been suggested that their unusual departure from homeothermy mitigates the associated costs. No studies, however, have examined how sloth body temperature and metabolic rate vary with T a . Here we measured the oxygen consumption (VO2) of eight brown-throated sloths (B. variegatus) at variable T a 's and found that VO2 indeed varied in an unusual manner with what appeared to be a reversal of the standard homeotherm pattern. Sloth VO2 increased with T a , peaking in a metabolic plateau (nominal 'thermally-active zone' (TAZ)) before decreasing again at higher T a values. We suggest that this pattern enables sloths to minimise energy expenditure over a wide range of conditions, which is likely to be crucial for survival in an animal that operates under severe energetic constraints. To our knowledge, this is the first evidence of a mammal provisionally invoking metabolic depression in response to increasing T a 's, without entering into a state of torpor, aestivation or hibernation.

Pharmacokinetics of vandetanib: three phase I studies in healthy subjects.

BACKGROUND: Vandetanib is an orally available inhibitor of vascular endothelial growth factor receptor 2 and epidermal growth factor receptor and is rearranged during transfection tyrosine kinase activity. Development has included studies in non-small cell lung cancer and other tumor types. Accurate elimination kinetics were not determined in patient studies, and so the current human volunteer studies were performed to derive detailed kinetic data. OBJECTIVE: The aim of this study was to investigate pharmacokinetics, metabolism, excretion, and elimination kinetics after single oral doses of vandetanib in healthy subjects. METHODS: Three studies were conducted. In Study A (n = 23), cohorts of 8 subjects were randomized to receive double-blind, ascending doses of vandetanib (300-1200 mg) or placebo (6:2). Study B had a crossover design; subjects (n = 16) received vandetanib 300 mg under fed and fasted conditions. In Study C, subjects (n = 4) received [(14)C] vandetanib 800 mg. Blood samples were collected for pharmacokinetic analysis for up to 28 days after the dose (Studies A and B) and 42 days after the dose (Study C). Plasma (all studies) and urine (Study A only) samples were collected for determination of vandetanib concentrations. In Study C radioactivity was measured in plasma, blood, urine, and feces, and metabolites were identified chromatographically. Tolerability was evaluated by recording of adverse events, clinical chemistry, hematology and urinalysis parameters, vital signs, and ECGs (all studies). RESULTS: Study A: mean (SD) age 34.4 (6.9) years; 23/23 male; mean (SD; range) weight 80.6 (8.1; 62-97) kg. Study B: mean (SD) age 35.3 (8.4) years; 15/16 male; mean (SD; range) weight 80.7 (11.2; 57-100) kg. Study C: mean (SD) age 60.3 (7.4) years; 4/4 male; mean (SD; range) weight 78.0 (7.7l; 72-87) kg. Pharmacokinetic parameters were consistent across all studies (Studies A and C, vandetanib 800 mg: geometric mean CL/F, 13.1-13.3 L/h; geometric mean apparent volume of distribution at steady state [V(SS)/F], 3592-4103 L; mean t(½), 215.8-246.6 hours). Vandetanib was absorbed and eliminated slowly after single oral doses. AUC(0-∞) and C(max) were not significantly affected by ingestion of food. Median (range) T(max) was 8 (3-18) hours after food and 6 (5-18) hours after fasting. In plasma, concentrations of total radioactivity were higher than vandetanib concentrations at all time points, indicating the presence of circulating metabolites. Unchanged vandetanib and 2 anticipated metabolites (N-desmethylvandetanib and vandetanib N-oxide) were detected in plasma, urine, and feces. A further trace minor metabolite (glucuronide conjugate) was found in urine and feces. Approximately two thirds of the dose was recovered in feces (44%) and urine (25%) over 21 days, underlining the importance of both routes of elimination. Adverse events were reported by all subjects in Study A apart from 2 at a vandetanib dose of 300 mg; 12/15 (80%) and 14/16 (88%) subjects who took vandetanib under fed and fasted conditions, respectively, in Study B; and 2/4 (50%) subjects in Study C. No serious adverse events were reported. Increasing doses of vandetanib, in Study A, were associated with variable increases in systolic and diastolic blood pressures and variable increases from baseline in QTc interval. Hematuria was reported by 3 subjects (vandetanib 300 mg) in Study A. Small but consistent increases from baseline in serum creatinine were noted in subjects who received vandetanib in these studies. No other clinically important changes were observed in clinical chemistry, hematology and urinalysis parameters, vital signs, and ECGs in any of the studies. CONCLUSIONS: The pharmacokinetics of vandetanib after single oral doses to healthy subjects were defined and the metabolic pathway was proposed. Vandetanib was absorbed and eliminated slowly with a t(½) of ∼10 days after single oral doses. The extent of absorption was not significantly affected by the presence of food. Approximately two thirds of the dose was recovered in feces (44%) and urine (25%) over 21 days. Unchanged vandetanib and N-desmethyl and N-oxide metabolites were detected in plasma, urine, and feces. Vandetanib appeared to be was well tolerated in the populations studied.

Pharmacokinetic drug interactions with vandetanib during coadministration with rifampicin or itraconazole.

BACKGROUND: Vandetanib, an inhibitor of vascular endothelial growth factor receptor 2 (VEGFR-2), epidermal growth factor receptor (EGFR), and rearranged during transfection (RET), is a developmental oncology drug, that is in part metabolized by cytochrome P450 (CYP) 3A4. Clinical studies were performed to assess the potential for 3A4 inhibitors and inducers to affect exposure to vandetanib. OBJECTIVE: The aim of this study was to investigate the effects of a potent CYP3A4 inducer, rifampicin (Study A), and a potent CYP3A4 inhibitor, itraconazole (Study B), on the pharmacokinetics of a single 300 mg dose of vandetanib in healthy subjects. STUDY DESIGN AND SETTING: Two phase I, randomized, open-label, two-way crossover, single-center studies. PARTICIPANTS AND INTERVENTION: Study A: 18 healthy male subjects aged 21-44 years were randomized to receive each of the following two regimens, separated by a ≥6-week washout period: (i) oral rifampicin 600 mg/day on days 1-31 with a single oral dose of vandetanib 300 mg on day 10; and (ii) a single oral dose of vandetanib 300 mg on day 1. Study B: 16 healthy male subjects aged 20-44 years were randomized to receive each of the following two regimens, separated by a 3-month washout period: (i) oral itraconazole 200 mg/day on days 1-24 with a single oral dose of vandetanib 300 mg on day 4; and (ii) a single oral dose of vandetanib 300 mg on day 1. MAIN OUTCOME MEASURE: Blood samples for measurement of vandetanib (both studies) concentrations and its metabolites, N-desmethylvandetanib and vandetanib N-oxide (Study A only), were collected before and at various timepoints after vandetanib administration for up to 28 days (Study A) and 37 days (Study B). Pharmacokinetic parameters were determined using non-compartmental methods. The area under the plasma concentration-time curve from time 0 to 504 hours (AUC(504)) and maximum plasma concentration (C(max)) of vandetanib were compared in the presence and absence of rifampicin, and in the presence and absence of itraconazole. RESULTS: Study A: coadministration of vandetanib with rifampicin resulted in a statistically significant reduction in AUC(504) (geometric least square [GLS]mean ratio [vandetanib + rifampicin/vandetanib alone] 0.60; 90% CI 0.58, 0.63). There was no significant difference in C(max) of vandetanib (GLSmean ratio 1.03; 90% CI 0.95, 1.11). AUC(504) and C(max) of N-desmethylvandetanib increased by 266.0% and 414.3%, respectively, in the presence of rifampicin compared with vandetanib alone. Exposure to vandetanib N-oxide was very low compared with that of vandetanib, but was increased in the presence of rifampicin. Study B: coadministration of vandetanib with itraconazole resulted in a significant increase in AUC(504) (GLSmean ratio [vandetanib + itraconazole/vandetanib alone] 1.09; 90% CI 1.01, 1.18) and no significant change in C(max) (GLSmean ratio 0.96; 90% CI 0.83, 1.11). Vandetanib was well tolerated in both studies. CONCLUSIONS: Exposure to vandetanib, as assessed by AUC(504) in healthy subjects, was reduced by around 40% when a single dose was given in combination with the potent CYP3A4 inducer rifampicin. Because of this, it may be appropriate to avoid coadministration of potent CYP3A4 inducers with vandetanib. Vandetanib exposure was increased by about 9% when it was taken in combination with the CYP3A4 inhibitor itraconazole. It is unlikely that coadministration of vandetanib and potent CYP3A4 inhibitors will need to be contraindicated.