Pharmacokinetics and safety profiles of tadalafil/ tamsulosin HCl fixed-dose combination capsule under fasted and fed condition in healthy volunteers

Byung Hak Jin; Byung Won Yoo; Eun Sil Oh; Seungwon Yang; Jina Jung; Min Soo Park

doi:10.12793/tcp.2016.24.4.175

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Jin, Yoo, Oh, Yang, Jung, and Park: Pharmacokinetics and safety profiles of tadalafil/ tamsulosin HCl fixed-dose combination capsule under fasted and fed condition in healthy volunteers

Original Article

Translational and Clinical Pharmacology 2016;24(4):175-182.

Published online: 19 January 2016

DOI: https://doi.org/10.12793/tcp.2016.24.4.175

Pharmacokinetics and safety profiles of tadalafil/ tamsulosin HCl fixed-dose combination capsule under fasted and fed condition in healthy volunteers

Byung Hak Jin^1,², Byung Won Yoo², Eun Sil Oh¹, Seungwon Yang^3,⁴, Jina Jung⁵, Min Soo Park^∗,^1,^2,⁶

¹Department of Pharmaceutical Medicine and Regulatory Sciences, College of Medicine and Pharmacy, Yonsei University, Incheon 21983, Korea

²Department of Clinical Pharmacology and Clinical Trials Center, Severance Hospital, College of Medicine, Yonsei University, Seoul 03722, Korea

³Department of Pharmacy, College of Pharmacy, Yonsei University, Incheon 21983, Korea

⁴Yonsei Institute of Pharmaceutical Sciences, College of Pharmacy, Yonsei University, Incheon 21983, Korea

⁵Clinical Research Team, Hanmi Pharmaceutical Co.,Ltd., Seoul 05545, Korea

⁶Department of Pediatrics, College of Medicine, Yonsei University, Seoul 03722, Korea

^∗Correspondence: M.S. Park; Tel: +82-2-2228-0270, Fax: +82-2-2227-7890, E-mail: minspark@yuhs.ac

Received 19 August 2016 Revised 29 November 2016 Accepted 29 November 2016

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Co-administration of tadalafil and tamsulosin HCl in patients with benign prostate hyperplasia and erectile dysfunction is increasing in clinical settings. Development of fixed-dose combination (FDC) of tadalafil and tamsulosin HCl could contribute to improving patients’ adherence and treatment efficacy. We evaluated the pharmacokinetics and safety profiles of a newly developed fixed-dose combination capsule of tadalafil 5 mg/tamsulosin HCl 0.4 mg in comparison with co-administration of each formulation in healthy volunteers under fasted and fed conditions. Two randomized, open-label, single-dose, two-way, crossover studies were completed in 29 subjects under fasted condition, and 33 subjects under fed condition. Serial blood sample collection for PK analysis was conducted up to 72 hours after dosing, and PK parameters were calculated using non-compartmental analysis. Geometric mean ratios and 90% confidence intervals of the C_max and AUC_last were used to evaluate comparative bioavailability. In both fasted and fed condition studies, the bioequivalence was established. The most common adverse drug reactions were orthostatic hypotension and headache with no statistical difference between treatment groups. All subjects with orthostatic hypotension recovered at follow-up test. Although changes in vital signs from baseline were statistically significant, there were no subjects with systolic blood pressure < 90 mmHg and there were no clinically meaningful signs or symptoms associated. FDC of tadalafil and tamsulosin HCl can be an alternative to co-administration of individual drugs for providing better compliance. Changes in blood pressure should be kept in mind when tadalafil and tamsulosin HCl are co-administered in clinical settings.

Keywords: pharmacokinetics, tadalafil, tamsulosin HCl, fixed-dose combination

REFERENCES

1.Auffenberg GB., Helfand BT., McVary KT. Established medical therapy for benign prostatic hyperplasia. Urol Clin North Am. 2009. 36:443–59. v-vi.

2.Lee C., Kozlowski JM., Grayhack JT. Intrinsic and extrinsic factors controlling benign prostatic growth. Prostate. 1997. 31:131–138.

3.Garraway WM., Collins GN., Lee RJ. High prevalence of benign prostatic hypertrophy in the community. Lancet. 1991. 338:469–471.

4.Park HK., Park H., Cho SY., Bae J., Jeong SJ., Hong SK, et al. The prevalence of benign prostatic hyperplasia in elderly men in Korea: A community-based study. Kor J Urol. 2009. 50:843–847.

5.Bae WJ., Sohn DW., Kim SD., Kim SJ., Hong SH., Lee JY, et al. The correlation between cardiovascular risk factors and penile hemodynamic parameters in men with erectile dysfunction. Kor J Urol. 2009. 50:689–693.

6.Braun M., Wassmer G., Klotz T., Reifenrath B., Mathers M., Engelmann U. Epidemiology of erectile dysfunction: results of the 'Cologne Male Survey'. Int J Impot Res. 2000. 12:305–311.

7.McVary KT., Roehrborn CG., Kaminetsky JC., Auerbach SM., Wachs B., Young JM, et al. Tadalafil relieves lower urinary tract symptoms secondary to benign prostatic hyperplasia. J Urol. 2007. 177:1401–1407.

8.Oh SY., Min KS., Choi SH. Effects of prostate volume and lower urinary tract symptoms on erectile function. Kor J Urol. 2007. 48:24–28.

9.U. S. Food and Drug Administration. Flomax Capsules, 0.4mg Prescribing Information. Accessed 20 June 2016.http://www.accessdata.fda.gov/drugsatfda_docs/label/2005/020579s016lbl.pdf.

10.Montorsi F., Verheyden B., Meuleman E., Jünemann KP., Moncada I., Valiquette L, et al. Long-term safety and tolerability of tadalafil in the treatment of erectile dysfunction. Eur Urol. 2004. 45:339–344. discussion 344-345.

11.McMahon CG. Treatment of erectile dysfunction with chronic dosing of tadalafil. Eur Urol. 2006. 50:215–217.

12.U. S. Food and Drug Administration. CIALIS Highlights of Prescribing Information. Accessed 20 June 2016.http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/021368s20s21lbl.pdf.

13.Bechara A., Romano S., Casabé A., Haime S., Dedola P., Hernández C, et al. Comparative efficacy assessment of tamsulosin vs. tamsulosin plus tadalafil in the treatment of LUTS/BPH. Pilot study. J Sex Med. 2008. 5:2170–2178.

14.Reges R., Regadas R., Moraes F., Manoel O., Jamacaru F., Vagnaldo F, et al. The association of tamsulosin and daily tadalafil for the treatment of lower urianry tract symptoms is safe and effective? J Urol. 2012. 187:e507.

15.Forgue ST., Patterson BE., Bedding AW., Payne CD., Phillips DL., Wrishko RE, et al. Tadalafil pharmacokinetics in healthy subjects. Br J Clin Pharmacol. 2006. 61:280–288.

16.World Health Organization. Guidelines for registration of fixed-dose combination medicinal products, in WHO Technical Report Series. 2005.

17.Chapple CR. Selective alpha 1-adrenoceptor antagonists in benign prostatic hyperplasia: rationale and clinical experience. Eur Urol. 1996. 29:129–144.

18.de Mey C. Cardiovascular effects of alpha-blockers used for the treatment of symptomatic BPH: impact on safety and well-being. Eur Urol. 1998. 34(Suppl 2):18-28; discussion 47.

19.Yasukawa K., Swarz H., Ito Y. Review of orthostatic tests on the safety of tamsulosin, a selective alpha1A-adrenergic receptor antagonist, shows lack of orthostatic hypotensive effects. J Int Med Res. 2001. 29:236–251.

Figure 1.

Plasma concentration-time profiles for (A) tadalafil, (B) tamsulosin HCl in fasted condition study as a fixed-dose combination or concomitant administration of individual drugs. Data are shown as mean ± SD. FDC, fixed-dose combination; Reference, concomitant administration of individual drugs.

Figure 2.

Plasma concentration-time profiles for (A) tadalafil, (B) tamsulosin HCl in fed condition study as a fixed-dose combination or concomitant administration of individual drugs. Data are shown as mean ± SD. FDC, fixed-dose combination; Reference, concomitant administration of individual drugs.

Figure 3.

Changes in (A) systolic blood pressure, (B) diastolic blood pressure over time in fasted condition study. Data are shown as mean ± SD. R, concomitantly administrated as individual drugs; T, administered as a fixed-dose combination

Figure 4.

Changes in (A) systolic blood pressure, (B) diastolic blood pressure over time in fed condition study. Data are shown as mean ± SD. R, concomitantly administrated as individual drugs; T, administered as a fixed-dose combination

Table 1.

Demographics of study participants

Variables		Fasted Study			Fed Study	P-value
Variables	T-R (N=15)	R-T (N=15)	P-value	T-R (N=17)	R-T (N=18)	P-value
Age (years)	24.5 ± 4.3	24.9 ± 3.5	0.82	27.0 ± 5.7	30.9 ± 6.5	0.07
Height (cm)	175.1 ± 4.8	175.5 ± 5.8	0.52	176.2 ± 5.2	174.7 ± 4.5	0.84
Weight (kg)	67.7 ± 6.0	69.1 ± 5.4	0.84	70.0 ± 4.9	70.4 ± 6.6	0.37
BMI (kg/m²)	22.0 ± 1.8	22.4 ± 1.7	0.59	22.5 ± 1.1	23.0 ± 1.7	0.29

Notes: Data are summarized as arithmetic mean ± standard deviation. P-values were derived by Student's t-test. T-R, FDC followed by concomitant administration of individual drugs; R-T, concomitant administration of individual drugs followed by FDC

Table 2.

Pharmacokinetic parameters of tadalafil and tamsulosin HCl after a single oral administration given as fixed-dose combination or concomitant administration of individual drugs in both studies

Study Type	Parameter	Tadalafil			Tamsulosin HCl
Study Type	Parameter		FDC	Reference	Geometric Mean Ratio ^a(90% CI)	FDC	Reference	Geometric Mean Ratio ^a(90% CI)
		T_max (h)	1.0 [0.5-4.5]	1.5 [0.5-4.5]		4.5 [3.0-6.0]	4.5 [3.0-6.0]
		C_max (ng/ml)	103.80 ± 25.99	103.33 ± 21.24	0.99 (0.92-1.07)	15.38 ± 3.74	15.20 ± 4.12	1.02 (0.96-1.08)
	Fasted condition study (N=29)	AUC_last (ng·h/ml)	1835.35 ± 442.93	1877.44 ± 469.36	0.98 (0.93-1.03)	185.96 ± 62.01	180.46 ± 61.64	1.03 (0.98-1.09)
		AUC_inf (ng·h/ml)	2005.80 ± 589.04	2078.39 ± 695.02		193.54 ± 64.56	188.83 ± 66.68
		t_1/2 (h)	18.82 ± 5.61	19.56 ± 7.18		11.15 ± 2.87	12.45 ± 3.91
		CL/F (L/h)	2.70 ± 0.79	2.63 ± 0.76		2.30 ± 0.77	2.37 ± 0.80
		Vd/F (L)	69.51 ± 14.69	68.84 ± 11.55		35.98 ± 7.92	39.75 ± 10.27
		T_max (h)	4.0 [2.0-5.6]	2.75 [1.0-5.0]		5.0 [3.0-7.0]	5.0 [3.0-7.1]
		C_max (ng/ml)	91.13 ± 15.48	95.94 ± 18.54	0.95 (0.91-1.00)	10.43 ± 3.37	10.03 ± 2.46	1.02 (0.96-1.09)
	Fed condition study (N=32)	AUC_last (ng·h/ml)	2144.83 ± 626.33	2146.43 ± 553.55	0.99 (0.95-1.03)	144.20 ± 61.90	144.24 ± 60.00	0.99 (0.94-1.05)
		AUC_inf (ng·h/ml)	2485.43 ± 930.43	2459.07 ± 777.79		152.14 ± 64.12	153.45 ± 61.06
		t_1/2 (h)	22.43 ± 7.08	22.62 ± 6.19		12.47 ± 3.18	14.09 ± 10.19
		CL/F (L/h)	2.28 ± 0.81	2.22 ± 0.66		3.03 ± 1.11	2.94 ± 0.97
		Vd/F (L)	67.33 ± 11.29	68.22 ± 12.31		52.40 ± 19.91	56.54 ± 36.22

Notes: Data are summarized as arithmetic mean ± standard deviation except for T^_max, for which median [min-max] is presented. ^a Geometric mean ratio of fixed-dose combination to concomitant administration Abbreviations: CI, confidence interval; T^_max, time to C^_max; C^_max, the maximum concentration of drug; AUC^_last, area under the plasma concentration-time curve from the time of dosing to the last measurable concentration; AUC_inf, area under the plasma concentration-time curve from dosing time extrapolated to infinity; t_1/2, elimination half-life; CL/F, apparent clearance; Vd/F, apparent volume of distribution

Table 3.

Comparison of pharmacokinetic parameters of tadalafil and tamsulosin HCl after a single oral administration as a fixed-dose combination capsule in the fasted and fed conditions

Parameter	Tadalafil			Tamsulosin HCl
Parameter	Fasted Study (N=29)	Fed Study (N=32)	Fed/Fasted Geometric Mean Ratio (90% CI)	Fasted Study (N=29)	Fed Study (N=32)	Fed/Fasted Geometric Mean Ratio (90% CI)
T_max (h)	1.0 [0.5-4.5]	4.0 [2.0-5.6]		4.5 [3.0-6.0]	5.0 [3.0-7.0]
C_max (ng/ml)	103.80 ± 25.99	91.13 ± 15.48	0.89 (0.81-0.97)	15.38 ± 3.74	10.43 ± 3.37	0.67 (0.59-0.75)
AUC_last (ng∙h/ml)	1835.35 ± 442.93	2144.83 ± 626.33	1.16 (1.03-1.30)	185.96 ± 62.01	144.20 ± 61.90	0.76 (0.65-0.88)
AUC_inf (ng∙h/ml)	2005.80 ± 589.04	2485.43 ± 930.43		193.54 ± 64.56	152.14 ± 64.12
t_1/2 (h)	18.82 ± 5.61	22.43 ± 7.08		11.55 ± 2.87	12.47 ± 3.18
CL/F (L/h)	2.70 ± 0.79	2.28 ± 0.81		2.30 ± 0.77	3.03 ± 1.11
Vd/F (L)	69.51 ± 14.69	67.33 ± 11.29		35.98 ± 7.92	52.40 ± 19.91

Notes: Data are summarized as arithmetic mean ± standard deviation except for T_max, for which median [min-max] is presented. Abbreviations: CI, confidence interval; T_max, time to C_max; C_max, the maximum concentration of drug; AUC_last, area under the plasma concentration-time curve from the time of dosing to the last measurable concentration; AUC_inf, area under the plasma concentration-time curve from dosing time extrapolated to infinity; t_1/2, elimination half-life; CL/F, apparent clearance; Vd/F, apparent volume of distribution

Table 4.

The incidence of common adverse drug reactions

Adverse Drug Reaction	Treatment	Fasted Study	Fed Study	Total	P-value^#
Orthostatic hypotension	FDC	8/30 (26.7%)	3/34 (8.8%)	11/64 (17.2%)	0.059
	Reference	7/29 (24.1%)	4/34 (11.8%)	11/63 (17.5%)	0.059
	Total∗	12/30 (40.0%)	6/35 (17.1%)
Headache	FDC	3/30 (10.0%)	2/34 (5.9%)	5/64 (7.8%)	0.659
	Reference	2/29 (6.9%)	4/34 (11.8%)	6/63 (9.5%)	0.659
	Total∗	4/30 (13.3%)	6/35 (17.1%)
Dizziness	FDC	0/30	1/34 (2.9%)	1/64 (1.6%)	0.999
	Reference	0/29	1/34 (2.9%)	1/64 (1.6%)	0.999
	Total∗	0/30	2/35(5.7%)

Notes: the number of subjects with ADRs / total subjects (percentage). P-values were derived by chi-square test.

^∗ Subjects whose ADRs occurred in both treatment groups were counted once.

^# Statistical difference in the incidence of ADRs between studies in fixed-dose combination group was estimated.

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