Abstract
Aim
Darapladib is a potent and reversible orally active inhibitor of lipoprotein-associated phospholipase A2 (Lp-PLA2). The aim of the study was to assess the effects of severe renal impairment on the pharmacokinetics and safety/tolerability of darapladib compared with normal renal function.
Methods
This was an open label, parallel group study of darapladib following 10 day once daily 160 mg oral dosing in subjects with normal (n = 8) and severe renal impairment (estimated glomerular filtration rate <30 ml min–1 1.73 m–2, n = 8). Plasma concentrations of total and unbound darapladib as well as total darapladib metabolites were determined in samples obtained over 24 h on day 10.
Results
Plasma concentrations of total and unbound darapladib as well as all three metabolites were higher in subjects with severe renal impairment. Area under the plasma concentration vs. time curve between time zero and 24 h (AUC(0,24 h) and maximum plasma concentration (Cmax) of total darapladib in severely renally impaired subjects were 52% and 59% higher than those in the matched healthy subjects, respectively. Similar results were found with the darapladib metabolites. Darapladib was highly plasma protein bound with 0.047% and 0.034% unbound circulating in plasma in severely renally impaired and healthy subjects, respectively. Unbound plasma darapladib exposures were more than two-fold higher in severely renally impaired subjects than in healthy controls. Adverse events (AE) were reported in 38% of healthy subjects and 75% of severely renally impaired subjects, most of which were mild or moderate in intensity.
Conclusions
The results of this study showed that darapladib exposure was increased in subjects with severe renal impairment compared with healthy controls. However, darapladib was generally well tolerated in both groups.
Keywords: atherosclerosis, darapladib, pharmacokinetics, phospholipase A2, renal impairment
What is Already Known about this Subject
Darapladib is a novel lipoprotein-associated phospholipase A2 (Lp-PLA2) inhibitor currently being developed for the treatment of atherosclerosis and diabetic macular oedema.
The principal route of darapladib elimination is by hepatic metabolism with renal excretion being less than 0.5% of the administered dose. A previously conducted study showed that moderate hepatic impairment has little impact on darapladib exposure.
The pharmacokinetics of darapladib in renally impaired subjects have not been previously reported.
What this Study Adds
Effects of severe renal impairment on the pharmacokinetics and safety/tolerability of darapladib were evaluated for the first time. As shown by the results of this study, exposure to darapladib was increased in subjects with severe renal impairment.
Introduction
Darapladib is an orally active reversible inhibitor of lipoprotein-associated phospholipase A2 (Lp-PLA2). It is currently being developed for the treatment of atherosclerosis and diabetic macular oedema.
The principal routes of darapladib metabolism are hydroxylation of the cyclopenta pyrimidinone ring to produce M3 (SB-823094), N-deethylation to produce M4 (SB-553253) and removal of the 4-fluorophenyl methanethiol to produce M10 (SB-554008). The pharmacological activities of M3 and M4 are similar to that of darapladib, while that of M10 is about 100-fold less than that of parent. In previous clinical studies in healthy subjects, low plasma concentrations (<5% of parent darapladib area under the curve [AUC]) of M3, M4, and M10 were observed (unpublished data on file, Clinical Pharmacology Modeling and Simulation, GlaxoSmithKline, King Of Prussia, PA, USA). Given the low exposures relative to the parent compound, darapladib metabolites do not contribute significantly to the pharmacological activity of darapladib in humans.
Elimination of darapladib occurs primarily by hepatic metabolism as unchanged parent compound and renal excretion represents less than 0.5% of the administered dose. Although darapladib is extensively metabolized in the liver, with metabolites primarily excreted though the faeces 1, renal impairment can affect its systemic exposure through various mechanisms 2,3. Accumulating evidence has shown that renal impairment can lead to alterations in non-renal clearance by affecting drug metabolizing enzymes and transporters 3. These effects may result from uraemic toxins that accumulate in patients with impaired renal function. Metabolism of certain drugs could be inhibited in human hepatocytes by the uraemic toxin indoxyl sulfate 4 and CYP3A activity has been shown to be decreased in patients with end-stage renal disease 5. Consequently, many new agents (such as darapladib) often require evaluation of exposure changes in the presence of renal impairment despite renal elimination being a minor route of the overall elimination 3.
Considering that the therapeutic target patient populations for darapladib (atherosclerosis and diabetic macular oedema) are likely to include a significant number of patients with impaired renal function and that renal impairment may alter darapladib exposure, the present study was conducted to assess the effects of severe renal impairment on the pharmacokinetics and safety/tolerability of darapladib, compared with normal renal function.
Methods
Study design
This was a phase 1, open label, non-randomized study conducted from October 2012 to March 2013 at two investigative sites in the United States. The goals of the study were to assess the pharmacokinetics and safety/tolerability of consecutive once daily 160 mg oral doses of enteric-coated darapladib, an Lp-PLA2 (HSD-PLA2, also known as serine-dependent phospholipase A2, PAFAH2, ENSG00000158006) inhibitor 6, in subjects with severe renal impairment in comparison with matched healthy controls. This trial is registered with ClinicalTrials.gov (NCT01711723).
The FDA Guidance for Industry indicates that at least eight evaluable subjects per group should be enrolled in renal impairment studies 2. Therefore, eight subjects completed the current study in each group (severe renal impairment or healthy control). According to the most recent study in healthy subjects, the between subject coefficient of variation (CVb) for the area under the plasma concentration–time curve during a dosing interval of duration τ (AUC(0,τ) and the maximum observed plasma concentration (Cmax) of darapladib was 33.71% and 38.86%, respectively. Based on a CVb of 38.86% and a sample size of eight in each group, it was estimated that the half width of the 90% confidence interval (CI) for the ratio of means was no more than 40% of the point estimates.
Based on the dose ranging study previously conducted in coronary heart disease patients, 160 mg was chosen for this study based on the pharmacokinetic, pharmacodynamic and safety profile 7. Subjects were institutionalized from the day before the first dose, and assigned to receive darapladib 160 mg enteric-coated tablets daily for 10 consecutive days. Following their release, subjects were required to return to the unit 10 to 14 days after the last dose of study medication and again 28 to 42 days after the last dose of study medication for clinical assessments.
The investigators and sponsor complied with all regulatory requirements relating to safety reporting to regulatory authorities, institutional review boards (IRBs) and investigators. The study protocol was approved by independent IRBs at the respective study sites. (These included the Western Institutional Review Board [WIRB] for DaVita Clinical Research in Minneapolis, Minnesota, USA, WIRB protocol #20121734 and Independent IRB for Orlando Clinical Research Center in Orlando, Florida, USA, IRB protocol #201207569.) This study was conducted in accordance with Good Clinical Practice and all applicable regulatory requirements, as well as the guiding principles of the 2008 Declaration of Helsinki. All subjects gave written informed consent before enrolment, which included compliance with the requirements and restrictions listed in the consent form.
Population studied
Subjects were 18 to 75 years of age (inclusive) at the time of signing the informed consent. Recruitment included male and female subjects and of any ethnic origin, in both the severely renally impaired group and the healthy control group.
Severe renal impairment was defined by estimated glomerular filtration rate (eGFR) <30 ml min–1 1.73 m–2 using the Modification of Diet in Renal Disease (MDRD) equation. The MDRD equation was used because it is thought to be more accurate in determining renal function in subjects with chronic kidney disease (CKD). Matched healthy control subjects had an estimated creatinine clearance (eCLcr) ≥90 ml min–1 using the Cockcroft–Gault equation. Renal function was determined by eCLcr via the Cockcroft–Gault 8 equation, due to the fact that MDRD, though more accurate in CKD subjects, may underestimate GFR in healthy individuals up to 26% 9.
The group of healthy subjects was matched as closely as possible to the group of subjects with severe renal impairment for gender, age and body mass index (BMI) (gender 1: 1, age ±10 years and BMI ±20%). Renally impaired subjects were enrolled first and healthy controls were subsequently matched.
General exclusion criteria included clinically significant diseases or laboratory abnormalities (except parameters influenced by renal impairment), a history of alcohol or drug abuse within the past 6 months, blood donation or blood loss greater than 500 ml within a 56-day period, current use of oral or injectable strong cytochrome P450 3A4 (CYP3A4) inhibitor(s) or consumption of grapefruit (or grapefruit juice) less than 7 days before initiation of study drug. Women who were breastfeeding, pregnant, planned to become pregnant during the study, or who used oral, injected or implanted hormonal methods of contraception were also excluded. Additional exclusion criteria for participants with normal renal function included a positive pre-study hepatitis B surface antigen, positive hepatitis C antibody or positive hepatitis A immunoglobulin M (IgM) antibody result within 3 months of screening, a history of cholecystectomy or biliary tract disease or a history of liver disease with elevated liver function tests of known or unknown aetiology.
Assessments
Blood samples for the pharmacokinetic analysis of darapladib and its metabolites (M3, M4 and M10) were collected pre-dose on days 8, 9 and 10 as well as at the following post-dose time points on day 10: 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 18 and 24 h. Blood samples were taken via an indwelling cannula or by direct venipuncture, collected into an ethylenediaminetetraacetic acid (EDTA) tube, gently inverted and immediately placed on water ice or in a refrigerator. Within 1 h of sample collection, plasma was separated by refrigerated (4°C) centrifugation at 1500 to 2000 × g for a minimum of 10 min. Supernatant plasma (two aliquots of no more than 500 µl) was then transferred to a 1.4 ml Matrix tube and stored at –20°C before shipment for sample analysis. The pharmacokinetic samples were analyzed for total darapladib, unbound darapladib and total metabolites (M3, M4 and M10). Details of the assay methods, including the method for obtaining the unbound fraction of darapladib, have been previously published 10.
Pharmacokinetic analyses of the concentration–time data for plasma total and unbound darapladib and total M3, M4 and M10, were conducted using non-compartmental Model 200 (for extravascular administration) of WinNonlin® Professional Edition version 5.2 (Pharsight Corporation, Mountain View, CA, USA). Actual elapsed time from dosing was used to estimate all individual plasma pharmacokinetic parameters for evaluable subjects. The Cmax and the time at which Cmax was observed (tmax) were determined directly from the raw concentration–time data. The AUC(0,τ) and the area under the plasma concentration–time curve from time zero to the last quantifiable time point (AUC(0,t)) were calculated by a combination of linear and logarithmic trapezoidal methods. The linear trapezoidal method was used for all incremental trapezoids arising from increasing concentrations and the logarithmic trapezoidal method was used for those arising from decreasing concentrations. In addition, the pre-dose (trough) concentration (Cτ) was determined, where τ is the end of dosing interval.
Complete physical examinations, 12-lead electrocardiograms (ECGs) and clinical laboratory assessments were obtained at screening and on the day 20–24 follow-up visit (clinical laboratory assessments were also obtained on days –1 and 11). Safety evaluations assessed adverse events (AEs) and serious adverse events (SAEs), which were collected from the start of darapladib dosing until the final follow-up visit.
Statistical analysis
This study was designed to estimate the effects of renal impairment on the pharmacokinetics of darapladib. For the purposes of calculating summary statistics and for statistical analysis, the pharmacokinetic parameters, AUC(0,τ) and Cmax, were loge transformed. Following loge transformation, darapladib AUC(0,τ) and Cmax were separately analyzed using a mixed effects model with group (renally impaired or healthy controls) as fixed effect term in the model. Point estimates and associated 90% CI were back-transformed to provide point estimates and 90% CI for the ratios of geometric means of the pharmacokinetic parameters for the renally impaired group vs. the healthy control group. The tmax of darapladib was analyzed with the non-parametric Wilcoxon rank-sum test to compute point estimates and associated 90% CI for the median differences between the renally impaired group and the healthy control group. Trough concentrations were used to assess attainment of steady-state by visual inspection. No formal analysis of steady-state was performed. Pharmacokinetic parameters of plasma darapladib metabolites and unbound darapladib were similarly analyzed.
Results
Patient disposition and demographics
A total of 16 subjects, eight with severe renal impairment and eight matched healthy controls, were enrolled into the study and administered darapladib 160 mg once daily for 10 days. The healthy control and severely renally impaired groups were balanced with respect to demography and other baseline characteristics (Table1). The overall mean age was 60 years. The majority of subjects were male (75%) and White (69%). Albumin was within the normal range for all subjects. All eight subjects in the renally impaired group received concomitant medications during the study. None of the eight healthy controls received any concomitant medications. The most commonly used concomitant medications were amlodipine, acetylsalicylic acid and lisinopril. Most of these concomitant medications were ongoing at the start of the trial. Darapladib treatment compliance was 100% as confirmed by study staff responsible for administering all doses of medication during the study. All eight severely renally impaired subjects and eight healthy subjects successfully completed 10 days of repeat dosing with 160 mg of darapladib.
Table 1.
Disposition and demographics
| Demographics | Healthy | Severe renal impairment |
|---|---|---|
| Age (years), mean (SD) | 56.8 (6.71) | 62.5 (9.87) |
| Gender n (%) | ||
| Female | 2 (25) | 2 (25) |
| Male | 6 (75) | 6 (75) |
| BMI (kg m–2), mean (SD) | 25.70 (3.45) | 27.28 (4.71) |
| Height (cm), mean (SD) | 174.9 (5.72) | 171.4 (6.44) |
| Weight (kg), mean (SD) | 78.96 (13.99) | 80.36 (15.48) |
| Ethnicity, n (%) | ||
| Hispanic or Latino | 1 (12.5) | 0 |
| Not Hispanic or Latino | 7 (87.5) | 8 (100) |
| Race, n (%) | ||
| African American/African heritage | 2 (25) | 2 (25) |
| African American/African heritage and White | 1 (12.5) | 0 |
| White – White/Caucasian/European heritage | 5 (62.5) | 6 (75) |
| Renal function* (ml min–1), mean (SD) | 115 (19) | 20 (4) |
| Albumin (g l–1), mean (SD) | 40.9 (4.5) | 40.3 (4.6) |
SD, standard deviation; BMI, body mass index.
As assessed by estimated creatinine clearance using Cockcroft-Gault equation in healthy subjects or estimated GFR using the MDRD equation in severely renally impaired subjects.
Safety
There were no SAEs or deaths reported in this study. A total of 29 AEs were reported in nine of 16 (56%) subjects during the study (Supplementary Table S1). Eight AEs were reported in three of eight (38%) healthy subjects and 21 AEs were reported in six of eight (75%) subjects with severe renal impairment. Most of these AEs were considered by the Investigator to be mild to moderate in intensity. The severe AE resolved in 1 day and did not result in discontinuation of study medication. Overall, diarrhoea was the most frequently reported AE with six episodes reported in four subjects (two subjects with severe renal impairment and two healthy subjects).
A total of 19 drug-related AEs (as determined by the Investigator) were reported in eight of 16 (50%) subjects during the study. Seven drug-related AEs were reported in two of eight healthy subjects (25%) and 12 drug-related AEs were reported in six of eight (75%) subjects with severe renal impairment. Most drug-related AEs were considered by the Investigator to be mild to moderate in intensity. Overall, the most frequently reported drug-related AE was diarrhoea with six episodes total in four subjects (two subjects with severe renal impairment and two healthy subjects).
There were a total of three haematology values of potential clinical importance (low platelet count, low total neutrophil count and low lymphocyte count). However, none of these abnormal values resulted in reporting of AEs. There were a total of 47 clinical chemistry values of potential clinical importance in eight subjects with severe renal impairment and there were none reported in the healthy subjects. Only one of these values was reported as an AE of an elevated creatinine in a subject with severe renal impairment which was resolved in 5 days. There were no vital signs values of potential clinical importance observed in this study. There were a total of 20 ECG values of potential clinical importance reported in five subjects with severe renal impairment. None of these was reported as AEs nor were they deemed as clinically significant by the Investigator.
Pharmacokinetic results
All 16 subjects enrolled were evaluable for darapladib pharmacokinetics. Individual plasma darapladib, M3, M4 and M10 concentrations were determined (Figure1), and selected pharmacokinetic parameters in severely renally impaired and healthy matched control subjects are summarized in Table2. Following the administration of multiple doses of 160 mg darapladib, the average AUC and Cmax values of darapladib and its metabolites were higher in the severely renally impaired subjects than in healthy subjects.
Figure 1.
Time course of plasma concentration of total darapladib (A), unbound darapladib (B), total M4 (C), total M10 (D) and total M3 (E) in healthy and severly renally impaired subjects following 10-day once daily oral dosing of 160 mg darapladib. 
healthy (mean + SD)
severely renally impaired (mean + SD)
Table 2.
Summary pharmacokinetic parameters of darapladib and its three metabolites following 10 day, once daily dosing of 160 mg of enteric-coated, micronized, free-base darapladib in severely renally impaired subjects and matched healthy control subjects
| Geometric LS Mean (CV%) | |||||
|---|---|---|---|---|---|
| Parameter (units) | Test | Reference | Ratio* | 90% CI | % CVb |
| Total darapladib | |||||
| AUC(0,τ) (ng ml–1 h) | 704.6 (48.9) | 465.1 (27.3) | 1.52 | (1.09, 2.11) | 39.3 |
| Cmax (ng ml–1) | 42.4 (55.6) | 26.7 (43.7) | 1.59 | (1.05, 2.40) | 49.8 |
| tmax (h) | 8 (6–10) | 7 (0–8) | 2 | (0, 6) | NE |
| M3 | |||||
| AUC(0,t) (ng ml–1 h) | 42.9 (141.4) | 18.8 (60.8) | 2.28 | (1.09, 4.79) | 101.3 |
| Cmax (ng ml–1) | 3.7 (168.7) | 2.1 (57.7) | 1.76 | (0.80, 3.91) | 112.4 |
| tmax (h) | 8 (4–10) | 6 (6–10) | 2 | (0, 2) | NE |
| M4 | |||||
| AUC(0,t) (ng ml–1 h) | 28.5 (94.7) | 14.6 (51.9%) | 1.95 | (1.09, 3.50) | 74.3 |
| Cmax (ng ml–1) | 2.4 (150.8) | 1.6 (71.1) | 1.52 | (0.69, 3.33) | 110.5 |
| tmax (h) | 8 (4–10) | 6 (6–10) | 0 | (–2, 2) | NE |
| M10 | |||||
| AUC(0,t) (ng ml–1 h) | 15.2 (52.9) | 7.5 (27.4) | 2.01 | (1.42, 2.86) | 41.6 |
| Cmax (ng ml–1) | 0.76 (52.7) | 0.51 (100.5) | 1.49 | (0.82, 2.73) | 77.7 |
| tmax (h) | 10 (3–24) | 10 (2–24) | 0 | (–7, 8) | NE |
| Unbound darapladib | |||||
| AUC(0,τ) (ng ml–1 h) | 0.33 (64.2) | 0.16 (65.3) | 2.13 | (1.26, 3.59) | 64.8 |
| Cmax (ng ml–1) | 0.02 (71.0) | 0.0090 (86.8) | 2.23 | (1.21, 4.11) | 79.0 |
| tmax (h) | 8 (6–10) | 7 (0–8) | 2 | (0, 6) | NE |
Estimated median difference presented for tmax.
CV, coefficient of variation; NE, not estimated.
For total darapladib, the AUC(0,τ) and Cmax in severely renally impaired subjects were 52% and 59% higher than that in the healthy control subjects, respectively. Darapladib was found to be highly plasma protein bound with 0.047% and 0.034% unbound darapladib circulating in plasma in severely renally impaired and healthy subjects, respectively. Exposures of unbound darapladib were increased in the severely renally impaired subjects with an average of 113% and 123% higher AUC(0,τ) and Cmax, as compared with healthy subjects, respectively. In addition, a high variability was observed in the pharmacokinetic parameters of unbound darapladib concentration. The coefficient of variation (CV%) of the pharmacokinetic parameters ranged between 65%–87%.
For the three metabolites of darapladib, exposures were also generally higher in severely renally impaired subjects than they were in healthy controls. For M3, M4 and M10, the ratio of severely renally impaired subjects versus healthy subjects for AUC(0,t) was 2.28, 1.95, 2.01 and for Cmax was 1.76, 1.52, 1.49, respectively. The exposures of metabolites were very low relative to parent exposure with the metabolite to parent AUC ratio being <7% on average for all three metabolites.
Following multiple doses, 160 mg darapladib was absorbed with delay with median tmax values of 8 and 7 h in subjects with severe renal impairment and normal renal function, respectively. This absorption delay is consistent with enteric coating. Concentrations of darapladib and its metabolites obtained at pre-dose on days 8, 9 and 10 were generally comparable between the 3 days within groups. Based on visual inspection, steady-state appears to have been generally achieved by day 10 in both groups for all analytes.
Discussion
The primary objective of the study was to characterize the pharmacokinetics of darapladib and its metabolites (M3, M4 and M10) following repeat 160 mg oral doses of darapladib in subjects with severe renal impairment vs. healthy matched control subjects. Severely renally impaired subjects were recruited based on an eGFR of <30 ml min–1 1.73 m–2 using the four variable MDRD equation. Healthy subjects with eCLcr ≥90 ml min–1 calculated by the Cockcroft–Gault equation using serum creatinine were then matched by age, gender and weight.
All eight severely renally impaired and eight healthy subjects successfully completed 10 days of repeat dosing with 160 mg darapladib. Plasma concentration profiles of all analytes (total and unbound darapladib, total M3, M4 and M10 metabolites) were higher in severely renally impaired subjects as compared with healthy matched controls (Figure1). These higher plasma concentration profiles translated to a 52%, 113%, 128%, 95% and 101% higher AUC in total and unbound darapladib, total M3, M4 and M10 metabolites in the severely renally impaired subjects, respectively.
In addition to CYP3A, darapladib is also a substrate for P-glycoprotein 1. Studies have shown conflicting effects of uraemia on P-glycoprotein activity in the intestine, kidney and liver 11–13. The higher levels of darapladib and metabolites seen in this study may be the result in part of increased oral bioavailability due to decreased intestinal P-glycoprotein activity.
Darapladib is a very highly protein bound molecule with protein binding >99.9%. Plasma unbound darapladib concentrations were determined with considerable effort given the very high plasma protein binding resulting in very low unbound darapladib concentrations. As stated in the Results section, only a subset of samples (three of 17 samples per subject) was directly analyzed for unbound darapladib concentrations. The degree of protein binding (%) in each sample was then calculated from the unbound and corresponding total concentrations. No concentration-dependent protein binding was apparent over the concentration range observed in this study (0.123 to 71.8 ng ml–1). Thus, an average of the three protein binding values was taken for each subject. Unbound darapladib concentration in the other 14 samples per subject was then calculated by multiplying the average protein binding value of that subject to the total darapladib concentration. A considerable portion of the unbound concentration–time profile was hovering around the lower limit of quantification (LLOQ) with Cmax being 9- and 20-fold of the LLOQ in the healthy and severely renally impaired subjects, respectively. High variability was observed in the pharmacokinetic parameters of unbound darapladib concentration. CV% of the pharmacokinetic parameters ranged between 65% and 87%. Overall, exposure to unbound darapladib was considerably higher in severely renally impaired subjects than that in the matched healthy controls, although the difference was observed with considerable ‘noise’ in the data.
Despite the considerable ‘noise’ in the data, a >2-fold increase in the exposure of unbound darapladib in the severely renally impaired subjects is likely a real signal. Based on pharmacokinetic data in healthy subjects following intravenous administration, darapladib is estimated to be a low hepatic extraction ratio drug. The unbound AUC of an orally administered low hepatic extraction ratio drug is dependent on the fraction of drug absorbed and intrinsic organ clearance of the drug 14. The change in unbound darapladib AUC may reflect an increased oral absorption due to decreased intestinal P-glycoprotein activity or a decreased metabolism in CYP3A activity or both processes in the severely renally impaired subjects. This is consistent with the accumulating evidence in the literature of the effects of renal impairment on the pharmacokinetics of drugs that are predominantly cleared by a non-renal mechanism 3. This emerging evidence in the literature and new drug application reviews ultimately triggered the modification of FDA guidance for industry 2. This current study may add to the collection of data on this important topic.
Another interesting observation in this study was the difference in magnitude of total vs. unbound darapladib exposure increase in subjects with severe renal impairment compared with subjects with normal renal function. Darapladib unbound AUC was 113% higher but total AUC was only 52% higher in severely renally impaired subjects. While protein binding does not influence exposure of orally administered unbound drugs for a low hepatic extraction ratio drug, the fraction unbound is inversely proportional to total AUC 14. Although the same underlying processes of absorption and/or metabolism may have caused an increase in both total and unbound AUCs of darapladib, the unbound fraction increase in severely renally impaired subjects compared with normal renal function subjects (0.047% vs. 0.034%, respectively) resulted in a smaller magnitude of change in total AUC compared with unbound AUC of darapladib.
For the three metabolites of darapladib, exposures were also generally higher in severely renally impaired subjects than they were in healthy controls. However, the concentrations of the metabolites were very low compared with parent darapladib (<7% of parent darapladib AUC for all three metabolites). Given that the pharmacological activities of the metabolites were similar to or less than that of the parent darapladib, the exposure differences between severely renally impaired subjects and healthy controls in metabolite exposure were unlikely to be clinically significant.
There were no unexpected safety findings. No deaths or SAEs occurred during this study and no subjects were withdrawn from the study due to AEs. The most common AE and the most common drug-related AE was diarrhoea, which occurred with the same frequency in both groups and has been observed in previous darapladib studies. No clinically significant changes in laboratory, vital sign or 12-lead ECG parameters were reported during the study.
This study evaluated the effects of severe renal impairment, compared with normal renal function, on the pharmacokinetics and safety/tolerability of oral repeat dosing of darapladib. Although a human radiolabel study had previously shown that less than 0.5% of the administered darapladib dose is eliminated by the renal route 1, severe renal impairment resulted in considerable reduction in darapladib overall clearance in total and unbound darapladib as well as in all three metabolites. Exposure increase was most pronounced in unbound darapladib exposure which is the entity presumably responsible for the pharmacological and toxicological actions of darapladib. Moreover, subjects with mild or moderate renal impairment were not evaluated in the current study. The population pharmacokinetic analysis of the phase 3 studies, in which patients with mild and moderate impairment participated, will bridge the gap in the knowledge on the overall impact of renal impairment on darapladib pharmacokinetics. The clinical implications of the findings from this study need to be assessed based on the future clinical development of darapladib.
Competing Interests
All authors have completed the Unified Competing Interest form at http://www.icmje.org/coi_disclosure.pdf (available on request from the corresponding author) and declare that the submitted work was sponsored by GlaxoSmithKline, PLC and all authors are currently full time employees of GlaxoSmithKline, PLC. There are no other relationships or activities have influenced the submitted work.
This study was funded by GlaxoSmithKline. The pharmacokinetic analyses were conducted by Covance Laboratories, Inc, under the direction of Clinical Pharmacology Modeling and Simulation, Quantitative Sciences, GlaxoSmithKline. The sponsors and authors thank the subjects who volunteered to participate in this study and acknowledge Ken Wiesen, PhD and Francesca Balordi, PhD (Medicus International, New York, NY, USA) for writing assistance and Courtney Breuel (PharmaWrite, Princeton, NJ, USA) for editorial and submission assistance, funded by GlaxoSmithKline. The sponsors and authors also thank the investigators: Dr Thomas C. Marbury from the Orlando Clinical Research Center (Orlando, FL, USA) and Dr Jolene Berg from DaVita Clinical Research (Minneapolis, MN, USA).
Author contributions
The authors made the following contributions: Mindy He Magee and Bonnie Shaddinger were responsible for conception and design, acquisition of data, and data analysis and interpretation. David Collins, Shabana Siddiqi and Joseph Soffer were responsible for conception and design and data analysis and interpretation. All authors reviewed the outline and drafts of the manuscript and have approved and are responsible for the submitted draft.
Supporting Information
Supporting info item
References
- Dave M, Nash M, Young GC, Ellens H, Magee MH, Roberts AD, Taylor MA, Greenhill RW, Boyle GW. Disposition and metabolism of darapladib, a lipoprotein-associated phospholipase A2 inhibitor, in humans. Drug Metab Dispos. 2014;42:415–30. doi: 10.1124/dmd.113.054486. [DOI] [PubMed] [Google Scholar]
- U.S. Food and Drug Administration. 2014. Guidance for industry: pharmacokinetics in patients with impaired renal function - study design, data analysis, and impact on dosing and labeling. Available at http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM204959.pdf (last accessed 23 September )
- Zhang Y, Zhang L, Abraham S, Apparaju S, Wu TC, Strong JM, Xiao S, Atkinson AJ, Jr, Thummel KE, Leeder JS, Lee C, Burckart GJ, Lesko LJ, Huang SM. Assessment of the impact of renal impairment on systemic exposure of new molecular entities: evaluation of recent new drug applications. Clin Pharmacol Ther. 2009;85:305–11. doi: 10.1038/clpt.2008.208. [DOI] [PubMed] [Google Scholar]
- Hanada K, Ogawa R, Son K, Sasaki Y, Kikkawa A, Ichihara S, Ogata H. Effects of indoxylsulfate on the in vitro hepatic metabolism of various compounds using human liver microsomes and hepatocytes. Nephron Physiol. 2006;103:179–86. doi: 10.1159/000092919. [DOI] [PubMed] [Google Scholar]
- Dowling TC, Briglia AE, Fink JC, Hanes DS, Light PD, Stackiewicz L, Karyekar CS, Eddington ND, Weir MR, Henrich WL. Characterization of hepatic cytochrome P4503A activity in patients with end-stage renal disease. Clin Pharmacol Ther. 2003;73:427–34. doi: 10.1016/s0009-9236(03)00056-0. [DOI] [PubMed] [Google Scholar]
- Wilensky RL, Shi Y, Mohler ER, III, Hamamdzic D, Burgert ME, Li J, Postle A, Fenning RS, Bollinger JG, Hoffman BE, Pelchovitz DJ, Yang J, Mirabile RC, Webb CL, Zhang L, Zhang P, Gelb MH, Walker MC, Zalewski A, MacPhee CH. Inhibition of lipoprotein-associated phospholipase A2 reduces complex coronary atherosclerotic plaque development. Nat Med. 2008;14:1059–66. doi: 10.1038/nm.1870. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Mohler ER, III, Ballantyne CM, Davidson MH, Hanefeld M, Ruilope LM, Johnson JL, Zalewski A. The effect of darapladib on plasma lipoprotein-associated phospholipase A2 activity and cardiovascular biomarkers in patients with stable coronary heart disease or coronary heart disease risk equivalent: the results of a multicenter, randomized, double-blind, placebo-controlled study. J Am Coll Cardiol. 2008;51:1632–41. doi: 10.1016/j.jacc.2007.11.079. [DOI] [PubMed] [Google Scholar]
- Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron. 1976;16:31–41. doi: 10.1159/000180580. [DOI] [PubMed] [Google Scholar]
- Rule AD, Larson TS, Bergstralh EJ, Slezak JM, Jacobsen SJ, Cosio FG. Using serum creatinine to estimate glomerular filtration rate: accuracy in good health and in chronic kidney disease. Ann Intern Med. 2004;141:929–37. doi: 10.7326/0003-4819-141-12-200412210-00009. [DOI] [PubMed] [Google Scholar]
- Magee MH, Shearn S, Shaddinger B, Fang Z, Glaser R. An effect of moderate hepatic impairment on the pharmacokinetics and safety of darapladib. Br J Clin Pharmacol. 2014;7:1014–21. doi: 10.1111/bcp.12436. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Sun H, Frassetto L, Benet LZ. Effects of renal failure on drug transport and metabolism. Pharmacol Ther. 2006;109:1–11. doi: 10.1016/j.pharmthera.2005.05.010. [DOI] [PubMed] [Google Scholar]
- Nolin TD. Altered nonrenal drug clearance in ESRD. Curr Opin Nephrol Hypertens. 2008;17:555–9. doi: 10.1097/MNH.0b013e3283136732. [DOI] [PubMed] [Google Scholar]
- Dreisbach AW. The influence of chronic renal failure on drug metabolism and transport. Clin Pharmacol Ther. 2009;86:553–6. doi: 10.1038/clpt.2009.163. [DOI] [PubMed] [Google Scholar]
- Benet LZ, Hoener BA. Changes in plasma protein binding have little clinical relevance. Clin Pharmacol Ther. 2002;71:115–21. doi: 10.1067/mcp.2002.121829. [DOI] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Supporting info item