- Linagliptin is an approved DPP-4 inhibitor for treating type 2 diabetes that exhibits non-linear pharmacokinetics. Tadalafil is a PDE-5 inhibitor used to treat erectile dysfunction that has linear pharmacokinetics. - A study was conducted in 10 healthy Egyptian males to investigate the pharmacokinetic drug interaction between linagliptin and tadalafil. Upon co-administration, tadalafil absorption was delayed, clearance decreased by 2-fold, volume of distribution decreased by 3-fold, and maximum concentration and total exposure increased by 2.5-fold. - Co-administration resulted in increased muscle pain in 10% of volunteers and

1. Introduction
 Linagliptin (LNG) is a selective, competitive dipeptidyl
peptidase-4 (DPP-4) inhibitor, that was recently approved in
2011 for the treatment of type II diabetes. 1
 It is rapidly absorbed (tmax ~1.5h), has a large volume of
distribution and a terminal phase half-life of ~131h. It shows
non-linear pharmacokinetics within the therapeutic dose range
(1-10 mg per day) due to protein binding saturation. It is
eliminated mainly unchanged in feaces. 2
 Chronic hyperglycemia affects mainly the vascular system in
the body, Microvascular, macrovascular and other organ
complications may result in erectile dysfunction.
 Tadalafil (TDL) is a potent, reversible, competitive PDE-5
inhibitors used in the treatment of erectile dysfunction. 3
 TDL exhibits linear pharmacokinetics in healthy subjects over
the dose range of 2.5 to 20 mg. It is 94% bound to plasma
proteins mostly albumin inactive metabolites are eliminated in
feaces with mean elimination phase half-life of ~ 17.5h. Its
mean apparent oral clearance is 2.5 L/h. 3
References
1. Mourad S.S. et al. J. Chro matogr Sci 2016 Jun 21 3.Gupta MA. J Clin Pharmacol. 2005 . 45: 987
2. Neumiller, J. and S. Setter. Clinical therapeutics 2012; 34:993
Methods
Objectives
To study the pharmacokinetic drug interaction between LNG
and tadalafil (TDL) in healthy Egyptian volunteers
STUDING THE POSSIBLE PHARMACOKINETIC INTERACTION BETWEEN
LINAGLIPTIN AND TADALAFIL IN HEALTHY EGYPTIAN MALES:
A PILOT STUDY
Sarah S. Mourad1, Eman I. El-Kimary1, Dalia A. Hamdy1,2 and Magda A. Barary1
1Faculty of Pharmacy, Alexandria University, Alexandria 21521, Egypt
2AbEx Health Services LTD, Edmonton, Alberta, Canada
Results
Conclusions
The PK parameters reported in the Egyptian population for the two drugs came in good accordance with those previously reported in Japanese
and other Caucasian populations. Smoking did not affect the PK parameters of any of the drugs in the Egyptian healthy volunteers. Upon co-
administration of a single TDL 20 mg tablet with LNG 5 mg tablet to healthy volunteers that were on 5 mg/day LNG for 12 days, a drug interaction
occurred at the absorption, tissue distribution and elimination levels resulting in increase in muscle pain and prolonged QTc interval. Thus it is
advisable for diabetic patients on LNG to be administered lower doses of TDL . In addition caution and monitoring should be taken for such
population that is already on other medications that also prolong the QTc interval.
.
Clinical trial design A Phase IV, open-label,
cross-over drug
interaction study between
LNG and TDL was
conducted at Ghabour
Hospital, Alexandria,
Egypt (April to September
2016)
 Ethical approval obtained
from ethical committee,
Alexandria University
 10 health Egyptian males
were enrolled. 5 smokers
and 5 non smokers
 Vital signs and drugs’
side effects were
measured. Non-
compartmental PK
methods were applied.
 Upon co-administration of both drugs, a drug
interaction occurred resulting in delayed
absorption peak, 2 folds decrease in Cl/f , 3 folds
decrease in Vd/f, and ~2.5 folds increase in Cmax
and AUC of TDL.
TDL alone and after coadministration with
multiple doses of LNG LNG single and multiple dosing in healthy
volunteers
Effect of Smoking on LNG and TDL single doses
Acknowledgement: This work is funded by Pharco
Pharmaceuticals.
TDL TDL +LNG
Cmax (mg/L) 0.263±0.128 0.662±0.517*
Tmax (h) 4.63±2.81 7.83±2.92*
AUC0–∞ [mg.h /L] 7.51±3.85 17.7±13.5*
AUC0–96h[mg.h /L] 6.68±3.14 17.7±13.4*
AUC0–24h [mg.h /L] 3.46±1.46 8.37±6.08*
λz (h-1) 0.033±0.018 0.054±0.021*
t ½ (h) 26.3±11.4 14.4±4.76*
CL/F (L/h) 3.53±2.14 1.61±1.01*
Vd/F (L) 112.0±40.7 35.9±27.4*
• Coadministration did not
affect the PK of LNG nor its
Blood glucose lowering
effectWash out period of 2 months
Phase II
Day 1 : 5 mg linagliptin
Blood sampling till 12h
ut period of 15 days
Phase II
Day 2-12 : 5 mg linagliptin
Blood sampling to measure trough concentration
ut period of 15 days
Phase II
Day 13: 5 mg linagliptin + 20 mg tadalafil
Blood sampling to measure trough concentration and till 96h
ut period of 15 days
Phase I
Day 1: 20 mg tadalafil
Blood sampling till 96h
#TDL data for 10 volunteers, TDL +LNG data for 9 volunteers
* Significant difference with p=0.05
TDL LNG
SM# NON-SM# SM# NON-SM#
Cmax + 0.229±0.111 0.296±0.147 7.68±6.55 7.71±3.65
Tmax (h) 4.7±4.07 4.5±1.02 2.90±3.46 2.16±2.55
Cmin
(ng/mL)
- - 2.71±1.04 3.12±1.02
AUC0–∞
[mg.h /L]
6.54±2.34 8.48±5.05 0.302±0.165 0.290±0.086
AUC0–96h
[mg.h /L]
5.84±1.95 7.52±4.09 - -
AUC0–24h
[mg.h /L]
3.16±1.19 3.75±1.77 0.074±0.036 0.090±0.032
λz (h-1) 0.026±0.009 0.040±0.022 0.013±0.003 0.016±0.004
t ½ (h) 29.73±9.41 22.88±13.12 55.25±12.63 45.68±12.93
CL/F (L/h) 3.37±1.12 3.68±3.00 22.03±14.67 18.45±5.58
Vd/F (L) 134.9±34.71 89.12±34.87 1591±765 1201±439
Effect of the drug interaction on the
pharmacodynamics of TDL and LNG
+ Cmax is measured in (mg/l) in TDL and in (ng/ml) in LNG
# 5 volunteers were smokers and 5 volunteers were non-smokers
 coadministration
resulted in 60%
increase in TDL
induced muscle pain
in 10% of the
volunteers and ~7%
increase in TDL
prolongation of QTc
interval.
Baseline TDL(1) LNG(1) LNG(7) LNG(13) LNG(17)
LNG Pharmacokinetics upon
coadministration with TDL