Abstract
AIMS
PF-734200 is a potent, selective inhibitor of DPP-IV. This two-part study evaluated the pharmacokinetics (PK) of oral 20 mg PF-734200 in subjects with varying degrees of renal insufficiency or with end-stage renal disease (ESRD) requiring chronic haemodialysis (HD). The study also assessed the HD clearance of PF-734200 in ESRD.
METHODS
Part 1 included subjects with normal renal function or renal insufficiency but not on HD. Subjects received a single dose of 20 mg PF-734200 while fasting and serum and urine samples were collected. In part 2, period 1, 1 h after HD, a single 20-mg dose was given to subjects with ESRD and serum samples were collected. After a 7-day washout, subjects received another dose followed by collection of serum samples (period 2), during which HD was initiated 4 h after dosing. Dialysate samples were collected to quantify amount of drug removed, from which HD clearance was calculated. The fraction of drug dialysed was calculated using an AUC-based method.
RESULTS
Systemic exposures of PF-734200 increased approximately 1.5-, 2.2-, 2.1- and 2.8-fold in subjects with mild, moderate, or severe renal insufficiency or ESRD, respectively, compared with subjects with normal renal function. The terminal half-life increased from 16.2 h in subjects with normal renal function to 36.6 h in subjects with ESRD. Approximately, 29% of PF-734200 in the body after a single-dose administration was dialysed by 4 h HD.
CONCLUSIONS
Systemic exposure of PF-734200 increases with decreasing renal function. The effect of HD on drug removal is modest.
Keywords: DPP-IV, PF-734200, pharmacokinetics, renal insufficiency
WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT
Data demonstrating the pharmacokinetics (PK), efficacy and tolerability of PF-734200, a potent DPP-IV inhibitor in subjects with normal renal function, have been published or presented.
WHAT THIS STUDY ADDS
This study provides better data on the PK of PF-734200 in subjects with varying degrees of renal insufficiency and in subjects with end-stage renal disease undergoing haemodialysis. In assessing the effects of renal impairment on the PK of PF-734200, this study provides evidence for potential dose adjustment of PF-734200 in patients with certain categories of renal impairment.
Introduction
PF-734200 (3,3-difluoro-pyrrolidin-1-yl)-[(2S,4S)-(4-(4-pyrimidin-2-yl-piperazin-1-yl)-pyrrolidin-2-yl]-methanone is a potent and selective inhibitor of dipeptidyl peptidase-IV (DPP-IV), which, when administered orally, improved glucose tolerance as assessed by a reduction in the maximal glucose excursion during an oral glucose tolerance test in preclinical models of diabetes mellitus [1].
A study in 27 healthy volunteers receiving single 0.3- to 300-mg doses of PF-734200 demonstrated inhibition of DPP-IV resulting in a 2.3-fold maximal increase in glucagon-like peptide-1 (GLP-1) [2]. In a phase 2 randomized, placebo-controlled, dose-ranging study of PF-734200 added to ongoing metformin monotherapy, doses of 5 to 20 mg produced statistically significant reductions in glycosylated haemoglobin after 12 weeks of treatment (Terra SG, et al., unpublished data).
Because PF-734200 is cleared primarily through renal elimination in humans [3] and kidney function often worsens as diabetes progresses [4], an open-label study was conducted to evaluate the pharmacokinetics (PK), safety and tolerability of a single 20-mg dose in subjects with varying degrees of renal function and in subjects with end-stage renal disease (ESRD) requiring chronic haemodialysis (HD). In addition, the study aimed to calculate the HD clearance of PF-734200 in subjects with ESRD.
Methods
Inclusion/exclusion criteria
Male or female subjects aged 18 to 77 years with body mass index (BMI) 18 to 40 kg m−2 inclusive and total bodyweight >50 kg were eligible for participation in this study. Subjects with a recent history (≤3 months) of myocardial infarction, unstable angina, coronary revascularization, stroke or transient ischaemic attack, and subjects with severe heart failure (NYHA Class IV), acute renal disease, renal transplant or liver disease were excluded.
For the duration of the study certain drugs were prohibited, including those known to be potent inhibitors of CYP3A, immunosuppressive agents, other DPP-IV inhibitors or GLP-1 analogues. Subjects with renal insufficiency needed to be on stable doses of non-excluded medications.
Part 1 of the study included subjects with normal renal function [creatinine clearance (CLcr) >80 ml min−1] and subjects with mild (CLcr >50 and ≤80 ml min−1), moderate (CLcr≥30 and ≤50 ml min−1) and severe renal insufficiency (CLcr <30 ml min−1) but not on HD. Subjects in the mild, moderate and severe renal function groups were matched to subjects with normal renal function with respect to age, gender and weight. CLcr was estimated based on the Cockcroft–Gault equation [5]:
Male,
 |
Female,
CLcr = 0.85 × calculation for male subjects.
Part 2 of the study included subjects with ESRD, regardless of CLcr, receiving HD therapy three times per week for ≥6 weeks.
Administration of treatments and PK sample collection
In part 1 of the study, subjects with normal to severely impaired renal function were given a single dose of 20 mg PF-734200 (4 × 5 mg tablets) following a fast of at least 4 h. Serum and urine PK samples were collected from all subjects. Serum samples were collected pre-dose and at post dose hours 0.5, 1, 2, 4, 8, 12, 16, 24, 48, 72, 96 and 120. Urine samples were collected pre-dose and during the following intervals post dose: 0–12, 12–24 and 24–48 h.
In part 2, subjects with ESRD received 4 h of HD using a Fresenius F-180 high-flux polysulfone dialyser (Fresenius Medical Care, Waltham, MA, USA), which has a surface area of 1.8 m2. Blood flow for all subjects was 300 ml min−1, with dialysate flow rate of 500 ml min−1. One hour after the HD session completed, subjects were given a dose of 20 mg PF-734200 and a series of serum PK samples were drawn (period 1). One week following the first dose, the same subjects were given another dose followed by collection of a series of serum PK samples (period 2). During period 2, HD was initiated 4 h after oral dosing.
Arterial and venous blood samples were collected during the dialysis, and dialysate samples were collected hourly to quantify drug removal by HD which was then used to calculate CLD. Dialysate samples were collected using specially made 60-l containers calibrated with litre marks. The dialysis machines very accurately delivered a dialysate flow rate of 500 ml min−1. As long as the 1-h collection matched up to the 30-l premeasured mark on the container, it was assumed to be 30 l and was not further individually measured. One portion (approx 20 ml) of each hourly sample was analysed for PF-734200 concentration as described below.
Pharmacokinetic and statistical analysis
Serum, blood and dialysate samples were analysed for PF-734200 concentrations at Alta Analytical Laboratory (El Dorado, CA, USA) using a validated, sensitive and specific liquid chromatography-atmospheric pressure ionization/tandem mass spectrometry method. The lower limit of quantification was 0.100 ng ml−1. Accuracy, expressed as between-day percentage relative error of estimated concentrations compared with theoretical quality control (QC) concentrations, was 4.5–8.4%. Precision, expressed as between-day coefficients of variation of the estimated concentrations of the QC samples, was <6.8%.
The following pharmacokinetic parameters were assessed for all subjects using standard non-compartmental methods and summarized by renal function group: area under the serum concentration–time profile from time 0 to the time of the last quantifiable concentration [AUC(0,last)], maximum observed concentration within the dosing interval (Cmax) and time for Cmax (tmax). Area under the serum concentration–time profile from time 0 extrapolated to infinite time [AUC(0,∞)] and terminal-half life (t1/2) were assessed for all subjects in part 1 of the study and for subjects with ESRD during period 1. The apparent unbound oral clearance (CLu/F, where F is the oral bioavailability of PF-734200), unbound renal clearance (CLur) and cumulative amount of unchanged drug recovered in urine during the collection interval (Ae) were assessed only for subjects in part 1 of the study.
For period 2 (ESRD subjects), CLD was calculated using the following relationship: CLD = AD/AUC(4,8 h), where AD is the cumulative amount of PF-734200 collected in dialysate over the dialysis period of 4 h [sum of (dialysis fluid concentration × sample volume) for each collection interval] and AUC(4,8 h) is the area under the serum PF-734200 concentration vs. time curve over this interval.
PF-734200 is not highly bound to plasma proteins as a previous in vitro dialysis study determined that the fraction of unbound PF-734200 in human serum was 0.885 (Pfizer, data on file). Consequently, this value of unbound fraction was used for the calculation of unbound clearance including both CLur and CLD.
The fraction of drug dialysed was calculated using an AUC-based method [6].
Median serum PF-734200 concentration vs. time plots were generated for each renal function group.
The relationship between CLu/F and CLcr (day 0) was evaluated using linear regression. Estimates of the slope and intercept, together with 90% confidence intervals (CI) and the coefficient of determination, were obtained from the model. Ratios and 90% CIs for adjusted geometric mean CLu/F for each group with renal insufficiency to the group with normal renal function were calculated. One-way analysis of variance (anova) of AUC(0,∞), AUC(0,tlast), Cmax, CLu/F and CLur was also used to compare each group with renal insufficiency (Test) to the group with normal renal function (Reference). A plot of CLu/F vs. CLcr (day 0) was constructed with a regression line, 90% confidence regions and vertical lines for the renal function group cut-off values.
Safety evaluations included clinical monitoring, vital signs (pulse rate, blood pressure), 12-lead electrocardiograms (ECGs), adverse events (AEs) and safety laboratory tests. Safety parameters were summarized descriptively where appropriate.
The final protocol and informed consent documentation were reviewed and approved by the Institutional Review Board at each of the investigational centres participating in the study.
Results
A total of 30 subjects enrolled in and completed the study. Subjects with normal renal function and those with mild, moderate and severe renal insufficiency had similar baseline characteristics (Table 1). Subjects with ESRD were younger on average and had a higher BMI. The ESRD group also had a higher percentage of male and Black subjects than the other groups.
Table 1.
Baseline characteristics
| Normal renal function (n = 6) | Mild renal insufficiency (n = 6) | Moderate renal insufficiency (n = 6) | Severe renal insufficiency (n = 6) | End-stage renal disease (n = 6) | |
|---|---|---|---|---|---|
| Male, n (%) | 2 (33.3) | 2 (33.3) | 1 (16.7) | 3 (50.0) | 5 (83.3) |
| Mean age (SD) (years) | 62.2 (6.4) | 67.8 (9.6) | 70.3 (6.0) | 68.8 (4.2) | 50.5 (7.2) |
| Range | 51–69 | 49–76 | 60–77 | 65–76 | 43–60 |
| Race, n (%) | |||||
| White | 5 (83.3) | 6 (100.0) | 5 (83.3) | 5 (83.3) | 1 (16.7) |
| Black | 0 (0.0) | 0 (0.0) | 1 (16.7) | 1 (16.7) | 5 (83.3) |
| Other | 1 (16.7) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) |
| Weight (kg) | |||||
| Mean (SD) | 75.4 (13.5) | 75.4 (12.4) | 72.4 (13.9) | 70.4 (12.0) | 103.2 (26.4) |
| Range | 59.9–93.8 | 58.5–87.1 | 54.9–91.6 | 50.8–79.9 | 70.3–137.8 |
| Body mass index (kg m−2) | |||||
| Mean (SD) | 28.3 (3.6) | 28.6 (6.3) | 28.3 (5.5) | 25.6 (3.2) | 31.9 (7.0) |
| Range | 21.4–30.8 | 22.3–39.2 | 20.7–36.2 | 20.6–29.6 | 23.1–40.2 |
| Creatinine clearance (ml min−1) | |||||
| Mean (SD) | 103.5 (16.5) | 64.8 (11.1) | 42.8 (5.8) | 25.3 (3.1) | NA |
| Range | 86–124 | 54–80 | 34–47 | 22–29 | |
| CV (%) | 16 | 17 | 14 | 12 |
CV, coefficient of variance; NA, not applicable.
Serum concentration–time profiles are shown in Figures 1 (linear-linear) and 2 (log-linear). As shown in Table 2, mean Cmax and median tmax did not change substantially among the groups. However, mean t1/2 of each group increased progressively with decreasing renal function from 16.2 h in subjects with normal renal function to 36.6 h in subjects with ESRD.
Figure 1.
Median concentration–time profiles by varying degrees of renal function (linear-linear). For subjects with ESRD, hour 168 of period 1 is hour 0 of period 2
Figure 2.
Median concentration–time profiles by varying degrees of renal function (log-linear). For subjects with ESRD, hour 168 of period 1 is hour 0 of period 2
Table 2.
Mean pharmacokinetic parameter values for PF-734200
| Normal renal function (n = 6) | Mild renal insufficiency (n = 6) | Moderate renal insufficiency (n = 6) | Severe renal insufficiency (n = 6) | End-stage renal disease Period 1 (n = 6) | |
|---|---|---|---|---|---|
| AUC(0, ∞) (ng ml−1 h) (CV, %) | 3694 (29) | 5662 (41) | 8073 (22) | 7846 (32) | 10 262 (36) |
| AUC(0,last) (ng ml−1 h) (CV, %) | 3684 (29) | 5627 (41) | 7898 (22) | 7689 (33) | 6 885 (34)* |
| CLu/F (ml min−1) (CV, %) | 111.8 (38) | 77.8 (45) | 48.8 (24) | 51.2 (24) | NC |
| Cmax (ng ml−1) (CV, %) | 407.5 (33) | 432.3 (30) | 422.3 (16) | 379.5 (23) | 368.3 (32) |
| tmax (h), median (range) | 0.77 (0.50–2.00) | 0.75 (0.50–2.00) | 1.50 (0.50–4.03) | 1.00 (0.50–2.00) | 1.55 (0.50–4.00) |
| t1/2 (h) (CV, %) | 16.2 (5) | 17.9 (9) | 22.8 (23) | 23.2 (20) | 36.6 (11) |
| CLur (ml min−1) (CV, %) | 45.2 (28) | 20.5 (38) | 15.2 (57) | 11.8 (28) | NC |
| Ae (µg) (CV, %) | 7.99 (20) | 5.63 (46) | 5.00 (38) | 4.00 (25) | NC |
tlast = 48 h vs. 120 h for all other groups.
Ae, cumulative amount of drug recovered unchanged in urine during the dosing interval; AUC(0,∞), area under the serum concentration–time profile from time 0 extrapolated to infinite time; AUC(0,last), area under the serum concentration–time profile from time 0 to the time of the last quantifiable concentration; CLu/F, apparent unbound clearance; CLur, unbound renal clearance; Cmax, maximum observed concentration within the dosing interval; CV, coefficient of variance; NC, not calculated; t1/2, terminal half-life; tmax, time for Cmax.
Exposures of PF-734200 [geometric mean of AUC(0,∞)] were increased approximately 1.5-, 2.2-, 2.1- and 2.8-fold in subjects with mild, moderate and severe renal insufficiency and in subjects with ESRD, respectively, compared with subjects with normal renal function (Table 3).
Table 3.
Summary of statistical analysis
| Geometric mean | |||
|---|---|---|---|
| Parameter | Test | Reference | Ratio* (%) (90% CI) |
| AUC(0,∞) (ng ml−1 h) | Mild, 5250.6 | Normal, 3542.1 | 148.2 (107.1, 205.3) |
| Moderate, 7902.4 | Normal, 3542.1 | 223.1 (161.1, 308.9) | |
| Severe, 7574.6 | Normal, 3542.1 | 213.8 (154.4, 296.1) | |
| ESRD (period 1), 9767.2 | Normal, 3542.1 | 275.7 (199.2, 381.8) | |
| Cmax (ng ml−1) | Mild, 416.5 | Normal, 384.4 | 108.4 (81.4, 144.3) |
| Moderate, 417.8 | Normal, 384.4 | 108.7 (81.7, 144.7) | |
| Severe, 371.1 | Normal, 384.4 | 96.6 (72.5, 128.6) | |
| ESRD (period 1), 354.0 | Normal, 384.4 | 92.1 (69.2, 122.6) |
Ratio of adjusted geometric means between test and reference. AUC(0,∞), area under the serum concentration–time profile from time 0 extrapolated to infinite time; CI, confidence interval; Cmax, maximum observed concentration within the dosing interval; ESRD, end-stage renal disease.
Furthermore, CLu/F of PF-734200 correlated with CLcr with a coefficient of determination of 0.39 (Figure 3). The relationship between estimates of CLu/F and CLCR appeared to be linear with a slope of 0.738 (90% CI 0.40, 1.08). The unbound non-renal clearance estimated from the intercept of that relationship was 28.7 ml min−1 (90% CI 6.10, 51.4).
Figure 3.
Regression and 90% confidence intervals of serum PF-734200 CLu/F vs. CLcr. Regression equation: CLu/F = 28.73344 + 0.738056 × CLcr, r2 = 0.3875. Slope P value =0.0012, intercept P value =0.0402. Mean (—); 90% confidence interval (– – –)
Results from part 2 of the study showed that PF-734200 was modestly removed by HD in subjects with ESRD. The CLD ranged from 99 to 132 ml min−1 (mean, 116.8 ml min−1). The mean fraction of drug in the body dialysed during a single 4-h dialysis session was 29.1% (coefficient of variation, 28.4%). No obvious rebound effect in serum concentrations of PF-734200 was observed after HD was stopped (Figure 2).
Safety and tolerability
In both parts of the study, PF-734200 was well tolerated in subjects with normal renal function and in subjects with all degrees of renal insufficiency. No deaths, serious adverse events (AEs) or withdrawals because of AEs were reported during this study. A total of 10 AEs were reported by nine subjects receiving PF-734200, all but one of which (moderate arthropod bite) were mild in intensity. Eight mild AEs in seven subjects were considered by the investigator to be treatment-related.
No new laboratory test abnormalities or clinically significant changes in vital signs or ECGs were found.
Discussion
In this single-dose study, the observed systemic exposures [AUC(0,∞)] of PF-734200 were increased in subjects with mild (1.5-fold), moderate (2.2-fold) and severe (2.1-fold) renal insufficiency, and in subjects with ESRD (2.8-fold) relative to that of subjects with normal renal function. This is consistent with the clearance mechanism of the drug, of which renal clearance is the major component.
As expected, CLu/F decreased with decrease in CLcr in a proportional manner (CLu/F = 28.7 + 0.738 × CLcr). It is estimated that, for subjects with mild, moderate and severe renal insufficiency, and in subjects with ESRD, CLu/F decreased about 1.4-, 1.6-, 2.6- and 3.6-fold, respectively, relative to subjects with normal renal function. In addition, the mean unbound non-renal clearance estimated from the intercept of this relationship was 28.7 ml min−1, indicating that there is a contribution to the elimination of this compound from a non-renal source. This is consistent with a previous observation where urine radioactivity accounted for only about 70% of total dose [3]. It is also worth noting that no marked changes in Cmax and tmax were observed with decreasing renal function. However, to achieve exposure of PF-734200 similar to that seen in subjects with normal renal function, dosage adjustment may be necessary for subjects with moderate or severe renal insufficiency, as well as in subjects with ESRD requiring HD.
A study of another DPP-IV inhibitor, sitagliptin, in subjects with renal insufficiency found similar exposure [AUC(0,∞)] alterations in patients with mild (1.6-fold increase) and moderate (2.26-fold increase) renal insufficiency [7]. However, exposure [AUC(0,∞)] of sitagliptin was increased to a greater extent in subjects with severe renal insufficiency and ESRD (3.8- and 4.5-fold respectively) compared with what was observed for PF-734200 in this study, and Cmax of sitagliptin was moderately increased. No reduction of sitagliptin dose is recommended for patients with mild renal insufficiency, but dose adjustment is recommended for patients with moderate to severe renal insufficiency or ESRD. In a separate study of the DPP-IV inhibitor saxagliptin, among subjects with moderate or severe renal impairment, the AUC values of saxagliptin and its active metabolite were up to 2.1- and 4.5-fold higher, respectively, than the AUC values in subjects with normal renal function [8].
In the present study, approximately 29.1% of PF-734200 in the body after a single-dose administration was dialysed by 4-h dialysis, with CLD ranging from 99 to 132 ml min−1 through a 1.8-m2 dialyser membrane. This degree of elimination is consistent with the low molecular weight, low plasma protein binding and high solubility/permeability of PF-734200 [1]. Moreover, as it is removed by HD to a modest extent, PF-734200 can be administered regardless of the timing of HD in patients with ESRD.
A single dose of 20 mg PF-734200 was well tolerated in this study. Subjects reported few AEs, and no new clinically significant clinical laboratory, vital sign or ECG abnormalities were noted.
Limitations
These findings are limited by the single-dose treatment design of the study with six subjects in each renal function group. However, we believe that data from this single-dose study are relevant in predicting the effect of renal impairment on PF-734200 on the multiple-dose pharmacokinetics of PF-734200, for three reasons. First, the pharmacokinetics of PF-734200 are linear between 0.3 mg and 200 mg, and most importantly are consistent between single-dose and chronic treatment [2, 9]. Second, PF-734200 had no effect on serum creatinine following 12 weeks of dosing to subjects with type 2 diabetes receiving background metformin treatment (Pfizer Inc., data on file). Third, the single-dose design is widely accepted by regulatory authorities and used when making dosing recommendation decisions in product labels. Nevertheless, the final recommendation regarding dose adjustment for subjects with renal impairment would involve a combination of both the current study results and pharmacokinetic analysis from additional longer-term clinical studies.
In conclusion, following a single dose, AUC(0,∞) of 20 mg PF-734200 increased with decreasing renal function, while Cmax and tmax did not change. This study showed that AUC(0,∞) values were up to 2.8-fold higher in subjects with moderate to severe renal insufficiency or ESRD compared with values in subjects with normal renal function. The effect of HD on drug removal is modest. To achieve serum concentrations of PF-734200 similar to those in subjects with normal renal function, reduced dosage may be necessary in subjects with moderate or severe renal insufficiency, as well as in subjects with ESRD requiring HD.
Competing Interests
HD, SGT, RAB, RW and TTN are employees of and hold stock in Pfizer Inc.; SLJ was an employee of Pfizer Inc. at the time the study was conducted and holds stock in the company. The study was funded by Pfizer Inc. Editorial support was provided by Mark Poirier and Nick Rusbridge of PAREXEL International and was funded by Pfizer Inc.
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