Margaret Salfi

Pharmacological blockade of the vanilloid receptor TRPV1 elicits marked hyperthermia in humans

&NA; The vanilloid receptor TRPV1 has been identified as a molecular target for the treatment of pain associated with inflammatory diseases and cancer. Hence, TRPV1 antagonists have been considered for therapeutic evaluation in such diseases. During Phase I clinical trials with AMG 517, a highly selective TRPV1 antagonist, we found that TRPV1 blockade elicited marked, but reversible, and generally plasma concentration‐dependent hyperthermia. Similar to what was observed in rats, dogs, and monkeys, hyperthermia was attenuated after repeated dosing of AMG 517 (at the highest dose tested) in humans during a second Phase I trial. However, AMG 517 administered after molar extraction (a surgical cause of acute pain) elicited long‐lasting hyperthermia with maximal body temperature surpassing 40 °C, suggesting that TRPV1 blockade elicits undesirable hyperthermia in susceptible individuals. Mechanisms of AMG 517‐induced hyperthermia were then studied in rats. AMG 517 caused hyperthermia by inducing tail skin vasoconstriction and increasing thermogenesis, which suggests that TRPV1 regulates vasomotor tone and metabolic heat production. In conclusion, these results demonstrate that: (a) TRPV1‐selective antagonists like AMG 517 cannot be developed for systemic use as stand alone agents for treatment of pain and other diseases, (b) individual susceptibility influences magnitude of hyperthermia observed after TRPV1 blockade, and (c) TRPV1 plays a pivotal role as a molecular regulator for body temperature in humans.

Pharmacokinetics, pharmacodynamics, and safety assessment of palifermin (rHuKGF) in healthy volunteers

Palifermin is a recombinant human keratinocyte growth factor approved to decrease the incidence and duration of severe oral mucositis in patients with hematologic malignancies who received myelotoxic therapy requiring hematopoietic stem cell support.

No Effect of Renal Function or Dialysis on Pharmacokinetics of Cinacalcet (Sensipar®/Mimpara®)

ObjectiveCinacalcet (cinacalcet HCl; Sensipar®/Mimpara®) is a calcimimetic that is a treatment for secondary hyperparathyroidism in patients with renal failure. The objective of this study was to assess the effects of renal function and dialysis on the pharmacokinetics and pharmacodynamics of cinacalcet.MethodsTwo open-label, single-dose (75mg) studies of cinacalcet were performed: study 1 examined 36 subjects who had renal function ranging from normal to requiring haemodialysis, and study 2 examined ten subjects who were receiving continuous ambulatory peritoneal dialysis. Cinacalcet plasma concentrations were determined using a liquid chromatography-mass spectrometry/mass spectrometry assay. Cinacalcet pharmacokinetics were assessed using noncompartmental analyses.ResultsFollowing single-dose administration of cinacalcet, there was no evidence of increasing exposure with increasing degree of renal impairment, and the pharmacokinetic profile was similar for all subjects regardless of whether they were receiving haemodialysis (no difference on dialysis or nondialysis days detected) or peritoneal dialysis. Protein binding of cinacalcet, determined in study 1 only, was similar in all groups and the level of renal function did not affect the pharmacodynamics (as determined by intact parathyroid hormone and calcium levels). No serious adverse events occurred during either study.ConclusionThe degree of renal impairment and mode of dialysis do not affect the pharmacokinetics or pharmacodynamics of cinacalcet. Therefore, the dose of cinacalcet does not need to be altered for degree of renal impairment or dialysis modality.

Pharmacokinetics of Cinacalcet Hydrochloride When Administered with Ketoconazole

Background and objectiveThe calcimimetic cinacalcet hydrochloride (cinacalcet) is used for treatment of patients with chronic kidney disease with secondary hyperparathyroidism, a population that commonly receives multiple concurrent medications. Cinacalcet is eliminated primarily via oxidative metabolism mediated, in part, through cytochrome P450 (CYP) 3A4. Thus, the potential for an inhibitor of CYP3A4 to alter the pharmacokinetics of cinacalcet is of clinical importance. The objective of this study was to evaluate the pharmacokinetics of cinacalcet during treatment with a potent CYP3A4 inhibitor, ketoconazole.Subjects and methodsTwenty-four healthy subjects were enrolled in an open-label, crossover, phase I study to receive a single oral dose of cinacalcet (90mg) alone and with 7 days of ketoconazole (200mg twice daily). Blood samples for pharmacokinetics were collected for up to 72 hours postdose. Cinacalcet plasma concentration-time data were analysed by noncompartmental methods. Pharmacokinetic parameters were analysed using a crossover ANOVA model that included subjects who completed both treatment arms.ResultsTwenty subjects completed both treatment arms. The mean area under the plasma concentration-time curve of cinacalcet increased 2.3-fold (90% CI 1.92, 2.67) [range 1.15- to 7.12-fold] and the mean maximum plasma concentration increased 2.2-fold (90% CI 1.67, 2.78) [range 0.904- to 10.8-fold] when administered with ketoconazole, relative to when administered alone. The time to reach the maximum plasma concentration was not significantly affected, and the terminal elimination half-lives were similar between treatments.ConclusionsCo-administration of a potent CYP3A4 inhibitor moderately increased cinacalcet exposure in study subjects. This suggests that clinicians should monitor parathyroid hormone and calcium concentrations when a patient receiving cinacalcet initiates or discontinues therapy with a strong CYP3A4 inhibitor.

Pharmacokinetics and pharmacodynamics of cinacalcet in hepatic impairment : phase I, open-label, parallel-group, single-dose, single-centre study.

AbstractBackground and objective:The calcimimetic cinacalcet lowers blood parathyroid hormone (PTH), calcium and phosphorus levels and calcium-phosphorus product in patients with chronic kidney disease receiving dialysis. Cinacalcet is metabolized primarily through oxidative and conjugative pathways. Hepatic disease has the potential to alter cinacalcet metabolism. Thus, it is important to establish the potential for altered cinacalcet metabolism according to the level of hepatic function. This study aimed to evaluate the pharmacokinetics and pharmacodynamics of cinacalcet in subjects with different degrees of hepatic function.Methods:This was a phase I, open-label, single-dose, parallel-group, single-centre study that included 24 subjects (six with normal hepatic function and six each with mild, moderate and severe hepatic impairment according to Child-Pugh criteria). Subjects were given a single 50 mg oral dose of cinacalcet. Blood samples were taken for pharmacokinetic (pre-dose and up to 120 hours post-dose) and pharmacodynamic (pre-dose and up to 72 hours post-dose) evaluations. Plasma concentrations of cinacalcet were determined using a validated normal phase turbo ion spray liquid chromatography-mass spectrometry/mass spectrometry assay. Serum ionized calcium levels were determined by standard biochemical measures, and PTH levels were determined using an immunometric intact PTH (iPTH) assay. The primary endpoints of the study were area under the concentration-time curve from 0 to time t (AUCt), AUC from 0 to infinity (AUC∞) and maximum plasma concentration (Cmax). Other pharmacokinetic parameters (time to Cmax [tmax], terminal half-life [t1/2β], total body clearance [CL/F] and protein binding) and the effect of cinacalcet on plasma PTH and serum calcium were secondary endpoints. Results: Total cinacalcet exposure (AUC∞) was comparable in subjects with normal hepatic function and mild hepatic impairment. In subjects with moderate and severe hepatic impairment, mean AUC∞ was 2.4- and 4.2-fold higher, respectively, than in healthy subjects. Cinacalcet t1/2β was 1.3- and 1.7-fold longer in subjects with moderate and severe hepatic impairment, respectively, compared with subjects with normal hepatic function. Mean Cmax and tmax, as well as protein binding, were similar in all groups. Consistent with the increase in cinacalcet exposure, decreases in iPTH tended to be greater and prolonged in subjects with moderate and severe hepatic impairment. In this study, cinacalcet was well tolerated.Conclusion:These data demonstrate that cinacalcet can be used without dose adjustment in patients with mild hepatic impairment. However, increased drug exposure observed in subjects with moderate to severe hepatic impairment indicates that iPTH and serum calcium levels should be monitored closely and physicians should be more cautious about dose titration in patients with moderate or severe hepatic impairment.

The Pharmacokinetics of Cinacalcet are Unaffected Following Consumption of High- and Low-fat Meals

Cinacalcet HCl reduces iPTH, serum calcium, serum phosphorus, and the calcium-phosphorus product in patients with chronic kidney disease and secondary hyperparathyroidism who are receiving dialysis, and reduces elevated serum calcium associated with primary hyperparathyroidism and parathyroid carcinoma. Cinacalcet is administered orally, and thus concomitant administration with food may affect its bioavailability. The objective of this study was to examine the effect of fat and caloric intake on cinacalcet exposure. This phase 1, randomized, open-label, single-dose, 3-period, 3-treatment, 6-sequence crossover study enrolled 30 healthy subjects (19 men, 11 women) to receive a single oral dose of cinacalcet HCl (Sensipar®/Mimpara®; Amgen Inc. Thousand Oaks, CA) (90 mg) on 3 separate occasions: following a high-fat, high-caloric meal, a low-fat, low-caloric meal, and a 10-hour fast. Blood samples were obtained predose and up to 72 hours postdose for pharmacokinetic (AUC∞, Cmax) and safety evaluations. Twenty-nine subjects completed all the 3 treatment conditions. The mean (90% confidence intervals) AUC∞ following high- and low-fat meals was increased by 68 (48 to 89)% and 50 (33 to 70)%, respectively, relative to fasting. The difference in mean AUC∞ between high- and low-fat meals was small [12 (9.9-26)%]. The mean tmax of cinacalcet was prolonged in fasting subjects (6 h) in relation to high-fat (4 h) and low-fat (3.5 h) fed subjects. The mean t1/2β was similar between treatment conditions. Adverse events (AE) were observed at a similar frequency across the treatment conditions [high fat (34%), low fat (23%), and fasting (31%)]; the type of AE did not differ among the treatment conditions. The most common treatment-related AEs were headache 6/30 (20%), nausea 5/30 (17%), and dyspepsia 4/30 (13%) subjects. Administration of cinacalcet with either high- or low-fat meals results in significant increases in exposure, relative to administration under fasting conditions. However, the small differences observed in exposure following the ingestion of the different types of meals suggest that although food has a significant effect, the type of food does not. The observed effect supports the labeling statement that cinacalcet be taken with food, or shortly after a meal.

Pharmacokinetics and Pharmacodynamics of Pegfilgrastim in Subjects With Various Degrees of Renal Function

A phase I study was conducted to evaluate the effects of renal function on the pharmacokinetics and pharmacodynamics (absolute neutrophil count [ANC]) of pegfilgrastim in nonneutropenic subjects. Thirty subjects categorized into 5 renal function groups (normal, mildly impaired, moderately impaired, severely impaired, and end‐stage renal disease) received 1 subcutaneous injection of pegfilgrastim at 6 mg. The ANC profiles after pegfilgrastim administration were similar across different renal function groups. No discernable correlation between pharmacokinetic parameter values and degree of renal impairment was observed; the mean values ranged from 147 to 201 ng/mL for Cmax and from 7469 to 8513 ng×h/mL for AUC. Results suggest that the kidney has no important role in the elimination of pegfilgrastim. Therefore, no dosage adjustment for renal impairment is indicated for pegfilgrastim.

Bioequivalence of Liquid and Reconstituted Lyophilized Etanercept Subcutaneous Injections

The objective of this study was to compare the pharmacokinetics of liquid and reconstituted lyophilized etanercept. This single‐center, open‐label study had a 2‐period crossover design in which 36 healthy subjects were randomly assigned in a 1:1 ratio to etanercept (liquid/lyo or lyo/liquid). The treatments were separated by 28 days. Blood samples were obtained predose and at 10 predetermined time points postdose. Serum concentrations were determined by enzyme‐linked immunosorbent assay. Noncompartmental pharmacokinetic parameters were analyzed using a standard crossover analysis of variance model. Thirty‐three subjects completed both treatment periods. Geometric mean values (adjusted) of area under the serum drug concentration‐time curve from time zero to the time of the final quantifiable sample, area under the serum drug concentration‐time curve from time zero to infinity, and maximum concentration obtained with the 50‐mg/mL liquid etanercept injection were 93.0%, 90.7%, and 98.5% of the respective parameters for 2 injections of 25 mg/mL reconstituted formulation. All associated confidence intervals were within the predefined equivalence interval of 80% to 125%. No differences in safety profiles of the 2 formulations were apparent. Liquid etanercept was bioequivalent to the reconstituted lyophilized etanercept formulation.

Pharmacokinetics of Palifermin Administered as the Standard Dose and as a Collapsed Dose in Patients with Hematologic Malignancies

Study Objective. To assess the pharmacokinetic profile of palifermin after intravenous dosing with either a collapsed dose of 180 μg/kg/day for 1 day or a standard dose of 60 μg/kg/day for 3 days, before and after myeloablative chemoradiotherapy and peripheral blood progenitor cell (PBPC) transplantation.

Effect of Renal Function on the Pharmacokinetics of Palifermin

Palifermin (ΔN23KGF) decreases the incidence, severity, and duration of oral mucositis. The objectives of this open‐label study were to evaluate the pharmacokinetics of single‐dose palifermin in subjects with varying degrees of renal function. A single 90‐mcg/kg intravenous dose of palifermin was administered to 31 subjects with varying levels of renal function (normal to requiring hemodialysis). Pharmacokinetic analyses were conducted using serum palifermin concentrations. There was considerable overlap in mean palifermin serum clearance among the groups, ranging from 318 to 495 mL/h/kg, indicating that the level of renal function did not affect clearance in humans; thus, no dose adjustment of palifermin is indicated for patients with renal dysfunction.