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.
The objectives of this study were to assess the safety, pharmacokinetics, and efficacy of pegylated interferon alfa-2b (PEG-Intron) plus ribavirin in patients with chronic hepatitis C. A total of 72 ...patients (35 men/37 women, age range 20-68 years) with clinically compensated chronic hepatitis C virus (HCV) were enrolled into this open-label, randomized, active controlled study. Patients received either PEG-Intron 0.35, 0.7, or 1.4 μg/kg subcutaneously weekly for 24 weeks alone, or in combination with ribavirin 600, 800, or 1,000 to 1,200 mg orally daily. Patients were evaluated during treatment and after a 24-week follow-up period for safety and efficacy. Detailed pharmacokinetic assessments were performed at weeks 1 and 4. PEG-Intron alone produced expected dose-related reductions in white cells, neutrophils and platelets. Addition of ribavirin reduced hemoglobin levels in a dose-related manner, did not further reduce PEG-Intron–induced decreases in neutrophil or white cell count, and increased platelet counts. Neutrophil function tests (C5a and FMLP migration, killing curves) were unaltered. Reported adverse events (flu-like symptoms, asthenia) were qualitatively similar in all dose groups. Anti-HCV activity, as measured by loss of detectable serum HCV RNA (i.e. <100 copies/mL) at the end of treatment (week 24) and after 24 weeks of follow-up (week 48) showed dose-response trends for PEG-Intron. At each PEG-Intron dose level, anti-HCV activity was higher in patients coadministered ribavirin than in patients treated with PEG-Intron monotherapy. There was no evidence of pharmacokinetic interactions with either drug. We conclude that the safety and tolerability of combined PEG-Intron/ribavirin and PEG-Intron alone were comparable. Combined PEG-Intron/ribavirin showed dose-related synergistic anti-HCV effects, which were numerically superior to those obtained with PEG-Intron monotherapy.
(Hepatology 2000;32:647-653.)
Background:
Cinacalcet hydrochloride (HCl) can be used to manage the secondary hyperparathyroidism of patients with chronic kidney disease. This study investigated the pharmacokinetics, ...pharmacodynamics, safety, and tolerability of cinacalcet HCl over a dose range of 25 to 300 mg/d in patients receiving dialysis.
Methods:
Hemodialysis patients were randomly assigned 4:1 to receive cinacalcet HCl or placebo in this double-blind study. Cinacalcet HCl doses were escalated weekly in 25-mg increments from 25 to 300 mg/d. Noncompartmental methods were used to analyze the pharmacokinetic parameters of cinacalcet (the free-base). The effects of cinacalcet concentration on plasma parathyroid hormone (PTH) and serum calcium levels were evaluated.
Results:
Of 23 patients enrolled (17 patients, cinacalcet HCl; 6 patients, placebo), 10 patients (8 patients, cinacalcet HCl; 2 patients, placebo) completed the study. Plasma concentration, median area under the plasma concentration-time curve from time 0 to 24 hours after dosing, and maximal plasma concentration (C
max) of cinacalcet increased with doses up to 200 mg once daily. Median oral clearance ranged from 222 to 599 L/h, and median time after dosing when C
max occurred ranged from 2 to 3 hours across all doses. The pharmacokinetics were linear over the 25- to 200-mg once-daily dose range, with no substantial increase in exposure at greater than 200 mg. Changes in plasma PTH concentrations correlated inversely with cinacalcet concentration. The concentration-effect relationship was well described by an inhibitory maximal effect model. Cinacalcet HCl was reasonably tolerated, and the incidence of adverse events was similar between groups (76%, cinacalcet; 80%, placebo). Gastrointestinal events were noted at greater doses and may be dose related.
Conclusion:
Cinacalcet HCl shows a dose-proportional increase in exposure over the range of 25 to 200 mg once daily in patients on hemodialysis therapy, and kinetics were linear up to 200 mg once daily. The incidence of adverse events was similar between groups.
Aims
The objectives of this study were to assess the safety, pharmacokinetic and pharmacodynamic profiles, and antiviral efficacy of pegylated interferon‐α2b monotherapy in patients with chronic ...hepatitis C.
Methods
Fifty‐eight patients (38 men, 20 women; age range, 25 to 65 years) with compensated chronic hepatitis C were enrolled in this open‐label, randomized, active controlled study. Patients received 0.035 to 2.0 μg/kg pegylated interferon‐α2b subcutaneously weekly or the active control, interferon‐α2b 3 million IU subcutaneously three times/week, for 24 weeks. Safety and antiviral efficacy assessments were performed during treatment and in a subsequent 4‐week follow‐up period. Detailed pharmacokinetic assessments were performed at weeks 1 and 4.
Results
Pegylated interferon‐α2b produced dose‐related reductions in white blood cells, neutrophils, and platelets, and dose‐related increases in oral temperature, serum neopterin, and serum 2′5′‐oligoadenylate synthetase activity, which were qualitatively similar to those produced by nonpegylated interferon‐α2b. Reported adverse events (flu‐like symptoms, asthenia) were qualitatively similar in pegylated interferon‐α2b– and nonpegylated interferon‐α2b–treated groups. Dose‐related antiviral activity, as measured by loss of detectable serum hepatitis C virus RNA (<100 copies/mL), was noted at the end of treatment and after 4 weeks of follow‐up. Both pegylated and nonpegylated interferon‐α2b were rapidly absorbed, with maximal concentrations occurring ~8 to 12 hours after dose administration. Pegylated interferon‐α2b had sustained maximal serum concentrations for 48 to 72 hours after dose administration, whereas nonpegylated interferon‐α2b concentrations declined rapidly. Volume of distribution for both compounds was similar (~1 L/kg). Pegylated interferon‐α2b elimination half‐life was approximately 10‐fold greater, and mean apparent clearance was one tenth that of nonpegylated interferon‐α2b.
Conclusions
Pegylated and nonpegylated interferon‐α2b safety and pharmacodynamic profiles were comparable. Pegylated interferon‐α2b demonstrated delayed clearance compared with nonpegylated interferon‐α2b, consistent with once‐weekly administration.
Clinical Pharmacology & Therapeutics (2000) 68, 556–567; doi: 10.1067/mcp.2000.110973
The 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.
Twenty-four healthy subjects were enrolled in an open-label, crossover, phase I study to receive a single oral dose of cinacalcet (90 mg) 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.
Twenty 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.
Co-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.
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.
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 (AUCinfinity, Cmax) and safety evaluations. Twenty-nine subjects completed all the 3 treatment conditions. The mean (90% confidence intervals) AUCinfinity 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 AUCinfinity 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 t1/2beta 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.
In vitro work has demonstrated that cinacalcet is a strong inhibitor of cytochrome P450 isoenzyme (CYP) 2D6. The purpose of this study was to evaluate the effect of cinacalcet on CYP2D6 activity, ...using desipramine as a probe substrate, in healthy subjects.
Seventeen subjects who were genotyped as CYP2D6 extensive metabolizers were enrolled in this randomized, open-label, crossover study to receive a single oral dose of desipramine (50 mg) on two separate occasions, once alone and once after multiple doses of cinacalcet (90 mg for 7 days). Blood samples were obtained predose and up to 72 h postdose.
Fourteen subjects completed both treatment arms. Relative to desipramine alone, mean AUC and C(max) of desipramine increased 3.6- and 1.8-fold when coadministered with cinacalcet. The t (1/2,z) of desipramine was longer when desipramine was coadministered with cinacalcet (21.0 versus 43.3 hs). The t (max) was similar between the regimens. Fewer subjects reported adverse events following treatment with desipramine alone than when receiving desipramine with cinacalcet (33 versus 86%), the most frequent of which (nausea and headache) have been reported for patients treated with either desipramine or cinacalcet.
This study demonstrates that cinacalcet is a strong inhibitor of CYP2D6. These data suggest that during concomitant treatment with cinacalcet, dose adjustment may be necessary for drugs that demonstrate a narrow therapeutic index and are metabolized by CYP2D6.
Cinacalcet (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.
Two open-label, single-dose (75 mg) 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.
Following 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.
The 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.
Background
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.
Methods
This randomized, double‐blind, placebo‐controlled study investigated the pharmacokinetics, pharmacodynamics, and safety of palifermin in healthy volunteers after single, escalating doses (60 to 250 μg/kg). Pharmacodynamic measurements (Ki67 staining) assessing buccal mucosal epithelial proliferation were performed at baseline and at 48 or 72 hours after dosing.
Results
Exposure to palifermin increased approximately dose proportionally, with a 3‐fold increase observed for a 4‐fold increase in dose. Palifermin concentrations decreased sharply during the first 0.5 to 1.5 hours after dosing, slightly increased or plateaued between 1.5 and 6 hours, and subsequently decreased. The overall mean systemic clearance and volume of distribution at steady state were 590 mL/h/kg and 2000 mL/kg, respectively. The mean half‐life ranged from 4.5 to 6 hours across the dose levels. The mean and SD ratio of Ki67 staining at 48 hours after dosing to baseline was 1.19 (0.24) for placebo, 2.02 (0.60) for 60 μg/kg, 3.04 (1.13) for 120 μg/kg, and 4.66 (0.77) for 250 μg/kg–treated groups.
Conclusion
Palifermin exhibited linear pharmacokinetics and caused dose‐dependent epithelial proliferation.
Clinical Pharmacology & Therapeutics (2006) 79, 558–569; doi: 10.1016/j.clpt.2006.02.011
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