Pharmacokinetics of finrozole (MPV-2213ad), a novel selective aromatase inhibitor, in healthy men

Abstract

Aims

To investigate the pharmacokinetics of finrozole (MPV-2213ad), a novel competitive aromatase enzyme inhibitor, in healthy male volunteers.

Methods

The study was an open, partly randomized cross-over study including 23 volunteers receiving single doses of 3, 9 mg or 30 mg of finrozole as tablets or solution with 14 days between the administrations. The highest dose was given as tablets only. Serum concentrations of finrozole were determined using high performance liquid chromatography combined with mass spectrometry.

Results

The mean time to peak serum concentration ranged from 2.5 to 3.1, and 0.6–0.7 h after tablets and solution, respectively. The C_max values increased as the dose increased. The calculated apparent mean elimination half-life (t_1/2,z) was approximately 3 h after the solution, and approximately 8 h after the tablet. The AUC(0,∞) after finrozole tablets increased proportionally from 3 mg to 9 mg and from 3 to 30 mg. The calculated relative mean bioavailabilities (AUC(0,∞)−ratio) for the 3 mg and 9 mg doses of finrozole as tablets were 89% and 78%, respectively.

Conclusions

The absorption of finrozole from the tablet formulation was relatively rapid, and the apparent elimination half-life was longer after the tablet than after the solution, probably reflecting overlap of the absorption with the elimination phase.

Introduction

The enzyme aromatase catalyses the conversion of androgen substrates to oestrogens in the final step of steroid biosynthesis. Inhibition of this rate-limiting enzyme blocks oestrogen biosynthesis in a variety of human cells and tissues, and reduces the concentrations of circulating oestrogen [1–4].

Finrozole (MPV-2213ad) is a novel, nonsteroidal, competitive inhibitor of aromatase and is being evaluated for the treatment of urinary symptoms in men. Earlier studies with finrozole have mainly focused on its pharmacodynamics and safety [5, 6]. A major finding was that finrozole causes a potent, dose-dependent suppression of serum oestradiol concentration. The objective of this study was to investigate the pharmacokinetics of finrozole after oral administration as tablets and solution in healthy male volunteers.

Methods

Subjects

Twenty-three healthy male volunteers [mean age 24.9 years (range 22–32 years), mean body mass index 23.2 kg m⁻² (range 20.3–28.4 kg m⁻²)], not using any medication, gave their written informed consent to participate in the study, which was approved by the Joint Commission on Ethics of Turku University and Turku University Central Hospital. The study was conducted at the research unit of Clinical Research Services Turku, University of Turku, Finland, according to the Good Clinical Practice (GCP) principles.

Study drugs

Finrozole tablets contained 3 mg each of MPV-2213ad. The composition of finrozole solution was either 3 mg or 9 mg of MPV-2213ad dissolved in 5% hydroxypropyl-β-cyclodextrin in water. The drugs were manufactured by Oy Galena Ltd, Kuopio, Finland.

Study design

The study had an open, partly randomized cross-over design, in which single oral 3, 9 or 30 mg doses of finrozole were given to the volunteers. At the two lowest doses finrozole was given either as tablets or solution, with 14 days between treatments. Owing to the low solubility of finrozole, the 30 mg dose was given only as tablets. Eight subjects were recruited for each dose level. However, one subject from the 9 mg dose group dropped out due to a vaso-vagal reaction before receiving the study drug.

Blood samples for the determination of serum finrozole concentrations were collected through an indwelling plastic cannula or by venepunctures at the following time points: time 0 (immediately before drug administration) and 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 16, 20, 24 and 32 h and 2, 3 and 5 days after drug intake. The blood specimens were drawn into glass tubes without additives, centrifuged and the sera were kept frozen at −70 ° C until analysis.

Biochemical analyses

Serum concentrations of finrozole were determined at Bioanalytical Research Services Turku, Department of Pharmacology and Clinical Pharmacology, University of Turku, using a liquid chromatography-triple quadrupole mass spectrometer (PE Sciex API 365 LC/MS/MS system, Perkin-Elmer Co., Norwalk, CT, USA). The limit of quantification of the method was 0.1 ng ml⁻¹ with the linear range from 0.1 to 40.0 ng ml⁻¹, and the limit of detection was 0.05 ng ml⁻¹. The average between batch precision (coefficient of variation) was 6% (n = 18).

Pharmacokinetic analysis

The pharmacokinetic calculations were performed with the PCNONLIN 4.2 computer program (Scientific Consulting Inc., Apex, NC, USA) by using a noncompartmental model. The following pharmacokinetic parameters were calculated for each subject: peak concentration (C_max), taken as the maximum concentration observed in serum; time to peak serum concentration (t_max) taken as the sampling time at which C_max was observed; the apparent half-life of the elimination phase (t_1/2,z) determined by log-linear regression of terminal serum concentration vs time values; area under the serum concentration vs time curve extrapolated from the last measurable concentration to infinity (AUC(0,∞)). The relative bioavailability of finrozole from tablets was given by the ratio AUC(0,∞) _(tablet)/AUC(0,∞) _(solution).

Statistical analyses

All data were entered into a SAS® database system (SAS Institute Inc., version 6.12, Gary, NC, USA). Statistical analyses were performed by using analysis of variance for both parallel-group and cross-over design at a two-sided 0.05 significance level. The dose-proportionality of the increase in AUC(0,∞) was tested by comparing the dose-corrected AUC(0,∞) values. The results are given as means and standard deviations.

Results

Pharmacokinetics

The pharmacokinetic data are presented in Table 1. C_max was lower after the tablets than after the solution. C_max in serum increased with dose both after tablets and solution (P < 0.001 and P < 0.001, respectively). The apparent calculated mean t_1/2,z was more than twice as long after tablets compared with solution. The lack of significant differences between the dose-normalized AUC(0,∞) values indicated that serum drug concentrations were proportional to dose. Figure 1 shows the individual AUC(0,∞) values. The calculated mean (s.d.) relative bioavailability of finrozole from tablets compared to the solution was 89% (± 34%) for the 3 mg and 78% (± 14%) for the 9 mg dose.

Table 1.

Mean (s.d.) pharmacokinetic parameters for finrozole after single oral 3, 9 or 30 mg doses as tablets or solution in healthy male subjects.

	Finrozole
	3 mg		9 mg		30 mg
Parameter	tablet	solution	tablet	solution	tablet
tmax (h)	2.94 (1.29)*	0.63 (0.23)	2.50 (0.58)*	0.71 (0.27)	3.13 (1.33)
	[95%CI: + 1.22, + 3.41]		[95%CI: + 1.20, + 2.37]
Cmax (ng ml–1)	2.11 (1.58)*	6.22 (1.73)	8.88 (3.28)*	36.87 (17.09)	18.20 (5.65)
	[95%CI: −5.98, −2.23]		[95%CI: −44.12, −11.86]
AUC(0,∞)(ng ml–1 h)	13.25 (9.03)	13.93 (3.79)	57.68 (17.88)*	75.54 (22.24)	118.23 (45.69)
	[95%CI: −5.32, + 3.96]		[95%CI: −27.61, −8.12]
AUC(0,∞)/dose	4.42 (3.01)	4.64 (1.26)	6.41 (1.99)*	8.39 (2.47)	3.94 (1.52)
	[95%CI: −1.77, + 1.32]		[95% CI: −3.07, −0.90]
t1/2,z (h)	8.36 (4.48)*	3.38 (3.31)	7.85 (2.53)*	2.86 (0.94)	7.71 (1.65)
	[95%CI: + 1.47, + 8.22] (1)		[95%CI: + 2.38, + 7.61]
AUC(0,∞)−ratio	88.69 (34.36)		77.68 (13.51)		–
	[95%CI: + 59.96, + 117.41]		[95%CI: + 65.19, + 90.17]

^*P <0.05, finrozole tablet vs solution at the 3 and 9 mg dose levels.

95% confidence intervals (CI) for the formulation (tablet vs solution) difference are given in brackets [].

¹Calculated for seven subjects, because elimination rate constant could not be estimated in one subject

AUC(0,∞)−ratio=tablet/solution.

Figure 1.

Individual AUC(0,∞) values (ng ml⁻¹ h) after different doses of finrozole (○=solution and •=tablets).

Discussion

In this study, the pharmacokinetics of finrozole were investigated for the first time in humans after clinically relevant doses. Reports of other nonsteroidal aromatase inhibitors have mainly focused on pharmacodynamics with only a few pharmacokinetic results [7–10] being available.

The results of the present study indicate that as expected, finrozole is absorbed at a slower rate into the systemic circulation from the tablet than from the solution. Nevertheless, the absorption of finrozole from tablets is relatively rapid with maximum serum concentrations occurring at 2.5–3 h after oral administration.

The apparent elimination half-life of finrozole was longer after the tablets than after the solution, which probably reflects an overlap of the absorption and elimination phases following ingestion of the tablet. The true elimination half-life of finrozole determined after intravenous injection, would be expected to be similar to that observed after ingestion of the solution. Unfortunately, owing to the poor solubility of finrozole, an intravenous formulation was not available to test this hypothesis. The increase in AUC(0,∞) was dose-proportional over the dosage range studied. However, wide interindividual differences in the AUC(0,∞) values were evident. The calculated mean relative bioavailability of finrozole from tablets was high (78–89%) when compared with the solution.