Michael Derks

Coadministration of Dalcetrapib With Pravastatin, Rosuvastatin, or Simvastatin: No Clinically Relevant Drug‐Drug Interactions

Dalcetrapib targets cholesteryl ester transfer protein and increases high‐density lipoprotein cholesterol (HDL‐C) levels. It is in clinical development for the prevention of cardiovascular events and will likely be used in combination with standard of care, including statins. Three crossover studies in healthy males investigated the pharmacokinetic drug‐drug interaction potential of 900 mg dalcetrapib and statins: two 3‐period studies (dalcetrapib plus pravastatin or rosuvastatin) and a 2‐period study (dalcetrapib plus simvastatin). Effect on lipids and safety were secondary end points. The 900 mg dose investigated is higher than the 600 mg dose currently being investigated in Phase III. Coadministration of dalcetrapib with pravastatin, rosuvastatin, or simvastatin was not associated with significant increases in statin exposure except for a 26% increase in rosuvastatin Cmax (90% CI 1.088 to 1.468) but not AUC0–24 (90% CI0.931 to 1.085). Dalcetrapib AUC0–24 and Cmax were not significantly altered by coadministration with pravastatin, and were significantly lower when dalcetrapib was coadministered with rosuvastatin or simvastatin compared with dalcetrapib alone. The HDL‐C increase with dalcetrapib was not compromised by coadministration with statins, and reduction in low‐density lipoprotein cholesterol with dalcetrapib coadministered with statins was greater than with statins alone. Dalcetrapib alone and coadministered with statins was generally well tolerated.

A single-center, open-label, one-sequence study of dalcetrapib coadministered with ketoconazole, and an in vitro study of the S-methyl metabolite of dalcetrapib

BACKGROUND Dalcetrapib (RO4607381/JTT-705) is currently under clinical investigation for the prevention of cardiovascular events. It inhibits the activity of cholesteryl ester transfer protein and has been reported to increase levels of high-density lipoprotein cholesterol. OBJECTIVE Because dalcetrapib is likely to be coadministered with agents that inhibit the cytochrome P450 (CYP) 3A4 isozyme, this study aimed to determine the effect of ketoconazole, a strong CYP3A4 inhibitor, on the pharmacokinetics of dalcetrapib. METHODS An open-label, 1-sequence study was conducted in 2 cohorts of healthy, nonsmoking male volunteers aged 18 through 65 years, with a body mass index of 18 to 32 kg/m(2). The first cohort received dalcetrapib 600 mg on days 1 and 7 and ketoconazole 400 mg on days 2 through 7, and, based on the results of a planned interim analysis, the second cohort received dalcetrapib 900 mg alone on days 1 and 7 and ketoconazole on days 2 through 7. Pharmacokinetic and safety parameters were assessed at specific times throughout the study. To confirm CYP involvement in the metabolism of the inactive metabolite dalcetrapib-S-methyl, in vitro studies were performed using human liver microsomes and recombinantly expressed CYP isoforms. RESULTS Of the 26 participants, 96% were white, with a mean age of 38.1 years and a mean weight of 78.6 kg. In the in vivo portion of the study, coadministration of ketoconazole with dalcetrapib 600 mg had no significant effect on any pharmacokinetic parameter of dalcetrapib. Coadministration of ketoconazole with dalcetrapib 900 mg was associated with significant decreases in the dalcetrapib C(max) (-23%; P = 0.002) and AUC(0-infinity) (-18%; P = 0.001) and a significant increase in oral clearance (22%; P = 0.001). Significant increases in the C(max) (P = 0.001) and AUC(0-infinity) (P < 0.001) of dalcetrapib-S-methyl were observed with coadministration of ketoconazole. The combination was generally well tolerated, with 32 of 35 adverse events (91.4%) being mild in intensity. The most frequent adverse events were headache (6/26 [23.1%] in the ketoconazole group; 4/18 [22.2%] in the group receiving dalcetrapib 900 mg plus ketoconazole) and diarrhea (4/26 [15.4%] in the ketoconazole group; 2/18 [11.1%] in the group receiving dalcetrapib 900 mg plus ketoconazole). The in vitro studies confirmed the involvement of CYP3A in the metabolism of dalcetrapib-S-methyl. CONCLUSIONS In this clinical study in healthy male volunteers, coadministration of dalcetrapib 600 mg with the CYP3A4 inhibitor ketoconazole was not associated with any significant changes in the pharmacokinetic parameters of the parent compound. Coadministration of dalcetrapib 900 mg with ketoconazole was associated with significant decreases in the dalcetrapib C(max) and AUC, contrary to the increases that would be expected if dalcetrapib were a substrate for CYP3A4. The combination of dalcetrapib and ketoconazole was generally well tolerated.

In vitro and in vivo assessment of the effect of dalcetrapib on a panel of CYP substrates

ABSTRACT Objective: The primary objective of this study was to investigate the drug–drug interaction potential of dalcetrapib on drugs metabolized via major cytochrome P450 (CYP) isoforms using both in vitro and clinical approaches. A secondary objective was to investigate the safety and tolerability of dalcetrapib alone or co-administered either with a combination of five probe drugs or with rosiglitazone. Research design and methods: Human liver microsomes and a panel of substrates for CYP enzymes were used to determine IC50 for inhibition of CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. In addition, two drug–drug interaction studies were conducted in healthy males: dalcetrapib 900 mg plus the Cooperstown 5 + 1 drug cocktail, which includes substrates for CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4, and dalcetrapib 900 mg plus rosiglitazone, a substrate for CYP2C8. Pharmacokinetic and safety parameters were assessed. Results: In vitro, dalcetrapib was inhibitory to all CYP enzymes tested. IC50 values ranged from 1.5 ± 0.1 μM for CYP2C8 to 82 ± 4 μM for CYP2D6. Co-administration of dalcetrapib plus drug cocktail showed no clinically relevant effect of 900 mg dalcetrapib on activity of CYP1A2, CYP2C19, CYP2D6, CYP2C9, or CYP3A4 following repeated administration. Co-administration of dalcetrapib plus rosiglitazone showed no clinically relevant effect of dalcetrapib 900 mg on activity of CYP2C8. Dalcetrapib was generally well tolerated. Conclusions: Although in vitro studies indicated that dalcetrapib inhibits CYP activity, two clinical studies showed no clinically relevant effect on any of the major CYP isoforms at a 900 mg dose, which is higher than the 600 mg dose being explored in phase III studies. Dalcetrapib was generally well tolerated in these studies. However, these studies were limited to a small number of healthy males; additional, larger studies are necessary to study its safety.

Effect of dalcetrapib, a CETP modulator, on non-cholesterol sterol markers of cholesterol homeostasis in healthy subjects.

OBJECTIVE Subjects with high HDL-C show elevated plasma markers of cholesterol absorption and reduced markers of cholesterol synthesis. We evaluated the effect of dalcetrapib, a cholesteryl ester transfer protein modulator, on markers of cholesterol homeostasis in healthy subjects. METHODS Dalcetrapib was administered daily with or without ezetimibe in a randomized, open-label, crossover study in 22 healthy subjects over three 7-day periods: dalcetrapib 900 mg, ezetimibe 10mg, dalcetrapib 900 mg plus ezetimibe 10mg. Plasma non-cholesterol sterols lathosterol and desmosterol (cholesterol synthesis markers) and campesterol, β-sitosterol and cholestanol (intestinal cholesterol absorption markers) were measured. A hamster model was used to compare the effect of dalcetrapib and torcetrapib with or without ezetimibe on these markers and determine the effect of dalcetrapib on cholesterol absorption. RESULTS Dalcetrapib increased campesterol, β-sitosterol, and cholestanol by 27% (p = 0.001), 32% (p < 0.001), and 12% (p = 0.03), respectively, in man (non-cholesterol sterol/cholesterol ratio). Dalcetrapib+ezetimibe reduced campesterol by 11% (p = 0.02); β-sitosterol and cholestanol were unaffected. Lathosterol and desmosterol were unchanged with dalcetrapib, but both increased with ezetimibe alone (56-148%, p < 0.001) and with dalcetrapib + ezetimibe (32-38%, p < 0.001). In hamsters, dalcetrapib and torcetrapib increased HDL-C by 49% (p = 0.04) and 72% (p = 0.003), respectively. Unlike torcetrapib, dalcetrapib altered cholesterol homeostasis towards increased markers of cholesterol absorption; cholesterol synthesis markers were unaffected by either treatment. Dalcetrapib did not change plasma (3)H-cholesterol level but increased (3)H-cholesterol in plasma HDL vs non-HDL, after oral dosing of labeled cholesterol. CONCLUSION Dalcetrapib specifically increased markers of cholesterol absorption, most likely reflecting nascent HDL lipidation by intestinal ABCA1, without affecting markers of synthesis.

Safety, Tolerability and Pharmacokinetics of Dalcetrapib Following Single and Multiple Ascending Doses in Healthy Subjects

AbstractBackground: Dalcetrapib is a modulator of cholesteryl ester transfer protein (CETP) activity developed to raise levels of high-density lipoprotein cholesterol (HDL-C) with the goal of further reduction of cardiovascular events additive to standard of care alone. In clinical studies, dalcetrapib has been shown to effectively increase levels of HDL-C with no significant safety concerns. Objective: The primary objective was to investigate the safety of single ascending and multiple ascending doses of dalcetrapib at doses markedly greater than that intended therapeutically (600 mg/day). Secondary objectives were to investigate the pharmacokinetics/pharmacodynamics and dose proportionality of dalcetrapib. Study Design: Randomized, double-blind, placebo-controlled, combined single and multiple ascending dose phase I study. Healthy males (age 18–65 years, body mass index 18–?2) were randomized to four of five dalcetrapib doses (2100,2700, 3300, 3900 or 4500 mg) or placebo, with ≥10 days washout between doses (n= 15, single ascending doses) or to dalcetrapib (1800, 2100, 3000 or 3900 mg once daily) or placebo for 7 days (four cohorts, each n= 10, randomization 8:2, multiple ascending doses). Main Outcome Measure: Tolerability and safety were assessed by monitoring adverse events (AEs), laboratory parameters, vital signs and 12-lead ECG recordings. Primary pharmacokinetic assessments were area under the plasma concentration-time curve (AUC) from time zero to infinity (AUC∞) and maximum observed plasma concentration (Cmax) [single doses] and AUC from time zero to 24 hours (AUC24) and Cmax (multiple doses). Pharmacodynamic assessments included CETP activity and lipids (multiple dosing only). Results: Exposure increased with dose but was less than proportional to increasing dose after single dosing, although deviation from dose proportionality could not be demonstrated for Cmax. Dose proportionality was consistent following multiple doses. Steady state was modelled to have been reached by approximately 4 days, with little to no accumulation. CETP activity reduction was dose dependent (maximum −55% after 3900 mg; placebo −2.6%) at 6 hours post-dose on day 1, while HDL-C increased by 12–19% (placebo −13%) on day 8 following treatment with 1800−3900 mg/day for 7 days. All AEs were mild or moderate in intensity and there were no serious AEs, deaths or withdrawals due to AEs. No clinically relevant effects on laboratory parameters, cardiac parameters or vital signs were noted. Conclusion: Single-dose dalcetrapib up to 4500 mg and multiple doses up to 3900 mg were generally safe and well tolerated.

Safety, tolerability and pharmacokinetics of dalcetrapib following single and multiple ascending doses in healthy subjects: a randomized, double-blind, placebo-controlled, phase I study.

BACKGROUND Dalcetrapib is a modulator of cholesteryl ester transfer protein (CETP) activity developed to raise levels of high-density lipoprotein cholesterol (HDL-C) with the goal of further reduction of cardiovascular events additive to standard of care alone. In clinical studies, dalcetrapib has been shown to effectively increase levels of HDL-C with no significant safety concerns. OBJECTIVE The primary objective was to investigate the safety of single ascending and multiple ascending doses of dalcetrapib at doses markedly greater than that intended therapeutically (600 mg/day). Secondary objectives were to investigate the pharmacokinetics/pharmacodynamics and dose proportionality of dalcetrapib. STUDY DESIGN Randomized, double-blind, placebo-controlled, combined single and multiple ascending dose phase I study. Healthy males (age 18-65 years, body mass index 18-32 kg/m2) were randomized to four of five dalcetrapib doses (2100, 2700, 3300, 3900 or 4500 mg) or placebo, with ≥10 days washout between doses (n = 15, single ascending doses) or to dalcetrapib (1800, 2100, 3000 or 3900 mg once daily) or placebo for 7 days (four cohorts, each n = 10, randomization 8 : 2, multiple ascending doses). MAIN OUTCOME MEASURE Tolerability and safety were assessed by monitoring adverse events (AEs), laboratory parameters, vital signs and 12-lead ECG recordings. Primary pharmacokinetic assessments were area under the plasma concentration-time curve (AUC) from time zero to infinity (AUC(∞)) and maximum observed plasma concentration (C(max)) [single doses] and AUC from time zero to 24 hours (AUC(24)) and C(max) (multiple doses). Pharmacodynamic assessments included CETP activity and lipids (multiple dosing only). RESULTS Exposure increased with dose but was less than proportional to increasing dose after single dosing, although deviation from dose proportionality could not be demonstrated for C(max). Dose proportionality was consistent following multiple doses. Steady state was modelled to have been reached by approximately 4 days, with little to no accumulation. CETP activity reduction was dose dependent (maximum -55% after 3900 mg; placebo -2.6%) at 6 hours post-dose on day 1, while HDL-C increased by 12-19% (placebo -13%) on day 8 following treatment with 1800-3900 mg/day for 7 days. All AEs were mild or moderate in intensity and there were no serious AEs, deaths or withdrawals due to AEs. No clinically relevant effects on laboratory parameters, cardiac parameters or vital signs were noted. CONCLUSION Single-dose dalcetrapib up to 4500 mg and multiple doses up to 3900 mg were generally safe and well tolerated.

No clinically relevant drug–drug interactions when dalcetrapib is co-administered with atorvastatin

Objectives: Dalcetrapib, which targets cholesteryl ester transfer protein, is in clinical development for prevention of cardiovascular events and is likely to be used concomitantly with statins. Two studies investigated co-administration of dalcetrapib with atorvastatin and any effects of the timing of atorvastatin on the pharmacokinetics of dalcetrapib. Research design and methods: Two crossover studies were performed in healthy subjects: a two-period study of dalcetrapib 900 mg concurrently with atorvastatin (concurrent dosing study) and a three-period study of dalcetrapib 600 mg (dose chosen for Phase III) with atorvastatin concurrently or serially 4 h after dalcetrapib (interval dosing study). Main outcome measures: The primary pharmacokinetic end points were AUC0 – 24 and Cmax; lipid effects and tolerability were secondary end points. Results: In the concurrent study (n = 26), co-administration reduced dalcetrapib AUC0 – 24 and Cmax and caused small changes in AUC0 – 24 and Cmax of atorvastatin and its active metabolites. In the interval study (n = 52), serial and concurrent co-administration of atorvastatin resulted in similar reductions in dalcetrapib exposure that were comparable to those observed in the concurrent dosing study. Co-administration did not decrease the efficacy of dalcetrapib or atorvastatin and was generally well tolerated. Conclusions: These results indicate no clinically relevant interactions for co-administration of dalcetrapib with atorvastatin.

Effects of food intake on the pharmacokinetic properties of dalcetrapib: findings from three phase I, single-dose crossover studies in healthy volunteers.

BACKGROUND Preclinical studies have reported that the relative bioavailability of dalcetrapib, a modulator of cholesteryl ester transfer protein (CETP) inhibitor activity, was ∼60% higher when administered in the fed state compared with the fasting state. OBJECTIVE This article reports on 3 studies conducted to assess the effects of food intake, timing of administration with respect to meals, and meal size and content on the relative bioavailability of dalcetrapib in healthy male subjects. METHODS Three Phase I studies were performed in healthy subjects: (1) a 2-period crossover study of a single dose of dalcetrapib 900 mg administered in the fed and fasting states (fed versus fasting study [1999]); (2) a 3-period crossover study of a single dose of dalcetrapib 600 mg administered after a light morning meal, a standard evening meal, and a light evening meal (meal timing/size study [2005]); and (3) a 4-period crossover study of a single dose of dalcetrapib 600 mg administered 30 minutes after a high-fat meal or a standard evening meal, and 30 minutes before or 3 hours after the latter (high-fat meal study [2007]). Blood samples for pharmacokinetic analyses (AUC(0-36) or AUC(0-∞), C(max)) were collected up to 36, 144, and 96 hours after study drug administration in the fed versus fasting, meal timing/size, and high-fat meal studies, respectively. CETP activity was measured using a radioisotopic method in the fed versus fasting study and a fluorometric method in the meal timing/size and high-fat meal studies. Tolerability was assessed using monitoring of adverse events, laboratory parameters, vital signs, and ECG. RESULTS Six men were enrolled in the fed versus fasting study (mean age, 37 years; mean body mass index [BMI], 23.6 kg/m(2)). Dalcetrapib exposure was increased by 64% (AUC(0-36)) and 126% (C(max)) after administration in the fed state. Eighteen men were enrolled in the analysis of the effects of meal timing and size on the properties of dalcetrapib (mean age, 30.5 years; mean BMI, 25.1 kg/m(2)). When dalcetrapib was administered after a light morning or a light evening meal, comparable values were found for mean dalcetrapib AUC(0-∞) (7400 and 7860 ng·h/mL, respectively) and C(max) (589 and 552 ng/mL), whereas administration after a standard evening meal was associated with increased AUC(0-∞) (14.3%-14.7%) and C(max) (25.5%-35.3%). Forty-nine men were included in the analysis in the high-fat meal study (mean age, 32.3 years; mean BMI, 23.9 kg/m(2)). Compared with administration after a standard evening meal, administration after a high-fat evening meal was associated with increased AUC(0-∞) (34.9%) and C(max) (43.7%). Between-treatment differences in exposure within each study also were reflected in apparent differences in CETP activity. All treatments were generally well tolerated. CONCLUSIONS Dalcetrapib exposure was increased in the fed state and, to a lesser extent, was dependent on the size and fat content of the meal. Exposure was independent of dosing time. Dalcetrapib was generally well tolerated.

Lack of clinically relevant drug–drug interactions when dalcetrapib is co-administered with ezetimibe

AIMS Dalcetrapib, which targets cholesteryl ester transfer protein activity, is in development for prevention of cardiovascular events. Because dalcetrapib will likely be prescribed with other lipid-modifying therapies such as ezetimibe, a study was performed to investigate potential pharmacokinetic interactions between dalcetrapib and ezetimibe. Lipids changes and tolerability were secondary endpoints. METHODS Co-administration of dalcetrapib 900 mg (higher than the phase III dose) with ezetimibe was investigated in a three period, three treatment crossover study in healthy males: 7 days of dalcetrapib, 7 days of dalcetrapib plus ezetimibe, 7 days of ezetimibe alone. A full pharmacokinetic profile was performed on day 7 of each treatment. RESULTS Co-administration of dalcetrapib with ezetimibe was associated with minimal changes in dalcetrapib exposure compared with dalcetrapib alone. Least squares mean ratio (LSMR) (90% confidence interval) was 93.6 (87.1, 100.7) for AUC(0,24 h) and 99.0 (85.2, 115.0) for C(max) . Ezetimibe exposure was reduced with co-administration of ezetimibe with dalcetrapib compared with ezetimibe alone: LSMR 80.3 (74.6, 86.4) for AUC(0,24 h) and 88.9 (80.9, 99.9) for C(max) for total ezetimibe. High-density lipoprotein cholesterol increases associated with co-administration of dalcetrapib with ezetimibe (+29.8%) were comparable with those with dalcetrapib alone (+25.6%), while the reduction in low-density lipoprotein cholesterol with co-administration (-35.9%) was greater than with ezetimibe alone (-20.9%). Dalcetrapib was generally well tolerated when administered alone and when co-administered with ezetimibe. CONCLUSION Co-administration of dalcetrapib with ezetimibe was not associated with clinically significant changes in pharmacokinetic parameters or tolerability and did not diminish the lipid effects of either drug.

No clinically relevant drug-drug interactions when dalcetrapib is co-administered with a monophasic oral contraceptive (Microgynon® 30).

UNLABELLED Dalcetrapib, a cholesteryl ester transfer protein modulator, under development to increase high-density lipoprotein cholesterol and potentially decrease cardiovascular risk, will potentially be co-prescribed to women on oral contraceptive (OC). OBJECTIVE Assess the effect of dalcetrapib on the pharmacokinetics and ability to suppress ovulation of Microgynon® 30, a representative monophasic OC. MATERIALS AND METHODS A single-center, randomized, open-label, two-period crossover study in healthy women receiving monophasic OC. Subjects received Microgynon® 30 (ethinylestradiol 0.03 mg/levonorgestrel 0.15 mg) once daily for 21 days followed by 7 treatment-free days (run-in period), then were randomized to Microgynon® 30 daily for 21 days with or without dalcetrapib 900 mg daily for Day 1 - 14. Plasma ethinylestradiol and levonorgestrel were measured on Day 14, and luteinizing hormone, follicle stimulating hormone, progesterone and estrogen from Day 11 - 14. The primary endpoint plasma exposure (AUC0-24 and Cmax) on Day 14 was evaluated for ethinylestradiol and levonorgestrel. Safety was monitored throughout. RESULTS 30 subjects were randomized. The exposure of ethinylestradiol and levonorgestrel was similar when Microgynon® 30 was administered with or without dalcetrapib; for ethinylestradiol the geometric mean ratio %, (90% confidence interval (CI)) for AUC0-24 and Cmax were 92 (86 - 98) and 105 (95 - 115) and for levonorgestrel 92 (88 - 96) and 93 (87 - 99), respectively. Concentrations of luteinizing hormone, follicle stimulating hormone, estrogen and progesterone were comparable between treatments. CONCLUSIONS Dalcetrapib has no clinically relevant effect on the pharmacokinetics of ethinylestradiol and levonorgestrel. Contraceptive efficacy of Microgynon® 30 is not anticipated to be compromised by co-administration of dalcetrapib.