Clinical Pharmacokinetics and Pharmacodynamics of Solifenacin

Doroshyenko, Oxana; Fuhr, Uwe
May 2009
Clinical Pharmacokinetics;2009, Vol. 48 Issue 5, p281
Academic Journal
The succinate salt of solifenacin, a tertiary amine with anticholinergic properties, is used for symptomatic treatment of overactive bladder. Solifenacin peak plasma concentrations of 24.0 and 40.6 ng/mL are reached 3-8 hours after long-term oral administration of a 5 or 10mg solifenacin dose, respectively. Studies in healthy adults have shown that the drug has high absolute bioavailability of about 90%, which does not decrease with concomitant food intake. Solifenacin has an apparent volume of distribution of 600 L, is 93-96% plasma protein bound, and probably crosses the blood-brain barrier. Solifenacin is eliminated mainly through hepatic metabolism via cytochrome P450 (CYP) 3A4, with about only 7% (3-13%) of the dose being excreted unchanged in the urine. Solifenacin metabolites are unlikely to contribute to clinical solifenacin effects. In healthy adults, total clearance of solifenacin amounts to 7-14 L/h. The terminal elimination half-life ranges from 33 to 85 hours, permitting once-daily administration. Urinary excretion plays a minor role in the elimination of solifenacin, resulting in renal clearance of 0.67-1.51 L/h. Solifenacin does not influence the activity of CYPIA1/2, 2C9, 2D6 and 3A4, and shows a weak inhibitory potential for CYP2C 19 and P-glycoprotein in vitro; however, clinical drug-drug interactions with CYP2C 19 and P-glycoprotein substrates are very unlikely. Exposure to solifenacin is increased about 1.2-fold in elderly subjects and about 2-fold in subjects with moderate hepatic and severe renal impairment, as well as by coadministration of the potent CYP3A4 inhibitor ketoconazole 200 mg/day. The full therapeutic effects of solifenacin occur after 2-4 weeks of treatment and are maintained upon long-term therapy. Although solifenacin pharmacokinetics display linearity at doses of 5-40 mg, no obvious dose dependency was observed in efficacy and tolerability studies. The efficacy of solifenacin (5 or 10 mg/day) is at least equal to that of extended-release (ER) tolterodine (4mg/day) in reducing the mean number of micturitions per 24 hours and urgency episodes, and in increasing the volume voided per micturition. Solifenacin (5 mg/day) appears to be superior to ER tolterodine (4mg/day) in reducing incontinence episodes (mean -1.30 vs -0.90, p=0.018) and is superior to propiverine (20mg/day) at the dose of 10mg/day in reducing urgency (-2.30 vs -2.78, p=0.012) and nocturia episodes. Based on withdrawal rates due to adverse effects during the 52-week treatment period, solifenacin appears to have better tolerability than immediate-release (IR) oxybutynin 10-15mg/day and IR tolterodine 4mg/day. With regard to the pharmacokinetics of solifenacin, and for safety reasons, doses exceeding 5mg/day are not recommended for patients with moderate hepatic impairment (Child-Pugh score 7-9), patients with severe renal impairment (creatinine clearance <30 mL/min) and subjects undergoing concomitant therapy with CYP3A4 inhibitors.


Related Articles

  • Modification of pharmacokinetics of norfloxacin following oral administration of curcumin in rabbits. Pavithra, B. H.; Prakash, N.; Jayakumar, K. // Journal of Veterinary Science;2009, Vol. 10 Issue 4, p293 

    investigation was carried out in adult New Zealand white rabbits to study the influence of curcumin pre-treatment on pharmacokinetic disposition of norfioxacin following single oral administration. Sixteen rabbits were divided into two groups of eight each consisting of either sex. Animals in...

  • A Perspective on Reconciling Mass Balance in Forced Degradation Studies. Lukulay, Patrick; Hokanson, Gerard // Pharmaceutical Technology;Oct2005, Vol. 29 Issue 10, p106 

    Focuses on two scenarios that demonstrate the need to use the percent of parent drug loss rather than the percent of degradation products formed when reconciling mass balance calculations. Quality control check on analytical methods to show that all degradation products are adequately detected...

  • Pharmacogenetics of CYP2C9 and interindividual variability in anticoagulant response to warfarin. Takahashi, H.; Echizen, H. // Pharmacogenomics Journal;2003, Vol. 3 Issue 4, p202 

    Summarizes clinical data on the relation between the CYP2C9 polymorphisms and the daily dose requirement of warfarin as well as the susceptibility to bleeding complications, and the impact of CYP2C9 polymorphisms on the pharmacokinetics of (S)-warfarin in different populations. Introduction to...

  • Pharmacokinetics and biodistribution of polymeric micelles of paclitaxel with Pluronic P123. Li-mei Han; Jie Guo; Li-jun Zhang; Qing-song Wang; Xiao-ling Fang // Acta Pharmacologica Sinica;Jun2006, Vol. 27 Issue 6, p747 

    Aim: To investigate the preparation, in vitro release, in vivo pharmacokinetics and tissue distribution of a novel polymeric micellar formulation of paclitaxel (PTX) with Pluronic P123. Methods: The polymeric micelles of paclitaxel with Pluronic P123 were prepared by a solid dispersion method....

  • Pharmacokinetics. Vohr, Hans-Werner // Encyclopedic Reference of Immunotoxicology;2005, p495 

    A definition of the term "pharmacokinetics" is presented. It refers to the study of bodily absorption, distribution, metabolism, and excretion of drugs.

  • Application of Scaling Factors in Simultaneous Modeling of Microarray Data from Diverse Chips. Zhenling Yao; Baiteng Zhao; Eric Hoffman; Svetlana Ghimbovschi; William Jusko // Pharmaceutical Research;Apr2007, Vol. 24 Issue 4, p643 

    AbstractPurpose??Microarrays have been utilized in many biological, physiological and pharmacological studies as a high-throughput genomic technique. Several generations of Affymetrix GeneChip?microarrays are widely used in gene expression studies. However, differences in intensities of signals...

  • Pharmacokinetics of an injectable long-acting formulation of doxycycline hyclate in dogs. Guti‚rrez, Lilia; Velasco, Zazil-Ha; V zquez, Carlos; Vargas, Dinorah; Sumano, H‚ctor // Acta Veterinaria Scandinavica;2012, Vol. 54 Issue 1, p35 

    Based on its PK/PD ratios, doxycycline hyclate (DOX-h), a time-dependant antibacterial, is ideally expected to achieve both sustained plasma drug concentrations at or slightly above the MIC level for as long as possible between dosing intervals. Pursuing this end, a poloxamer-based matrix was...

  • Zero-order Kinetic.  // Encyclopedic Reference of Molecular Pharmacology;2004, p1017 

    A definition of the term "Zero-order Kinetic" is presented. It refers to the time course of disappearance of drugs from the plasma, which do not follow an exponential pattern, but are initially linear. This rare time course of elimination is most often caused by saturation of the elimination...

  • Pharmacokinetics and Biotransformation of Mirtazapine in Human Volunteers. Delbressine, L.P.C.; Moonen, M.E.G.; Kaspersen, E.M.; Wagenaars, G.N.; Jacobs, P.L.; Timmer, C.J.; Paanakker, J.E.; van Hal, H.J.M.; Voortman, G. // Clinical Drug Investigation;1998, Vol. 15 Issue 1, p45 

    This paper investigated the pharmacokinetics and biotransformation of mirtazapine in healthy human volunteers. The results showed that the area under the plasma drug concentration- time curve (AUC ) of mirtazapine in human plasma appeared to be three times higher than the AUC of...


Read the Article


Sorry, but this item is not currently available from your library.

Try another library?
Sign out of this library

Other Topics