Vardenafil Preclinical Trial Data: Potency, Pharmacodynamics, Pharmacokinetics, and Adverse Events

Vardenafil preclinical trial data: potency, pharmacodynamics, pharmacokinetics, and adverse events

E Bischoff1*

1Bayer Pharma Research, Bayer HealthcareWuppertal, PH-R-EU-CV-ll, Wuppertal, Germany

Vardenafil potently inhibits human phosphodiesterase 5 (PDE5) with an IC50 of 0.7 nM. Enhancement of nitric oxide (NO)-induced erections in rabbits by 0.1 mg/kg vardenafil is limited by its pharmacokinetic properties (Tmax ¼ 1h; T1/2 ¼ 1.2 h), although erectile effects have been observed after 7 h. In humans, vardenafil is rapidly absorbed (Tmax E40 min) and more slowly E metabolized (T1/2 4 h), with an absolute bioavailability of 14.5% (vs 40% for sildenafil). Although the consumption of high-fat meals does not affect the drug’s relative bioavailability, it retards intestinal absorption. Coadministration of CYP3A4 inhibitors such as ritonavir can affect hepatic metabolism. M1, an active metabolite of vardenafil, is a four-fold-less potent inhibitor of PDE5 than its parent compound, contributing approximately 7% to vardenafil’s overall efficacy. The side effects of all selective PDE5 inhibitors commonly include vasodilation, small reductions in blood pressure, headache, and nasal congestion. International Journal of Impotence Research (2004) 16, S34–S37. doi:10.1038/sj.ijir.3901213

Keywords: 30,50-cyclic-GMP phosphodiesterase; selective phosphodiesterase inhibitors; muscle; smooth; penile erection; penis; human

Introduction pelvic nerve stimulation2 and in a rat model, displaying greater efficacy on erectile response than sildenafil at comparable doses.4 As mentioned previously, vardenafil exhibits high Efficacy in vivo not only depends on the potency potency in inhibiting PDE5, with an IC50 of 0.7 nM. and the selectivity of a particular PDE5 inhibitor, but Vardenafil increases intracellular cGMP in the also on its pharmacokinetic (PK) properties. They presence of sodium nitroprusside, an NO donor, in can be characterized by its absorption, distribution, both rabbit and human cavernosal tissue. In a direct metabolism, and excretion. In general, plasma comparison with sildenafil, vardenafil was proven concentrations of a compound correlate with its 1,2,3 effective at lower concentrations. Also, vardena- efficacy. Tmax, the time to achieve maximal plasma fil significantly potentiated both acetylcholine concentration (Cmax), often corresponds to the (Ach)-induced and transmural electrical stimula- maximal pharmacodynamic effects of a given phar- tion-induced relaxation of trabecular smooth macologic agent. muscle. In rabbits, oral vardenafil was eliminated from the As shown in a conscious rabbit model, the in vitro plasma at a half-life (T1/2) of approximately 1.2 h, efficacy of vardenafil has translated to similar more rapidly than the T1/2 of 4–5 hours observed efficacy in vivo. Vardenafil potentiated erectile in humans. In this model, the vardenafil plasma responses to intravenous sodium nitroprusside in concentration (Tmax ¼ 1 h) determined its initial conscious rabbits in a dose-dependent manner at efficacy in enhancing NO-induced erections. How- 1,3 doses of 0.1–3 mg/kg. The minimum dose re- ever, significant erectile responses persisted even quired for a significant erectile effect was deter- after 7 h (T1/2 Â 4) when plasma concentrations had mined to be 0.1 mg/kg. Vardenafil also demonstrated declined to 2.5%. This implies that in humans, effectiveness in an anesthetized rabbit model with vardenafil with a Tmax of approximately 40 min 5 could remain efficacious beyond one T1/2. Table 1 summarizes the most important PK *Correspondence: E Bischoff, PhD, Bayer Pharma Re- properties of vardenafil, sildenafil, and tadalafil. search, Bayer HealthcareWuppertal, PH-R-EU-CV-ll, D- Vardenafil’s absolute bioavailability is 14.5% com- 42096 Wuppertal, Bldg. 500, Germany. pared to 40% for sildenafil; the value for tadalafil is E-mail: [email protected] not yet published. Intestinal absorption of the drug Vardenafil: Preclinical data E Bischoff S35 can be influenced by nutrition. A high-fat meal duration of 460% penile rigidity were 37.2 min at delays the time to maximum plasma concentration, the base and 28.7 min at the tip. Plasma levels rose but does not alter vardenafil’s relative bioavailability rapidly after oral administration. Median Tmax was (B90%). Vardenafil, as well as sildenafil, undergo 0.9 h for the 10 mg dose and 0.7 h for the 20 mg dose. hepatic metabolism via the CYP3A4 pathway. Mean Cmax was 9.1 and 20.9 mg/l, respectively. The Therefore, concomitant administration of strongly average terminal plasma half-life (T1/2) was 4.2 h for CYP3A4-inhibiting drugs or drugs that are metabo- the 10 mg dose and 3.9 h for the 20 mg dose (Table 2). lized by this pathway can elevate plasma levels of The area under the curve (AUC), normalized for these PDE5 inhibitors. Moderate dosage adjustments both dose and body weight, was proportional to are required for patients using drugs such as dose. ritonavir concomitantly with vardenafil or sildena- Vardenafil was well tolerated. Its administration fil. Vardenafil is primarily excreted through the was associated with a small reduction in blood feces (91–95%), with minimal renal excretion of the pressure and a minor compensatory increase in drug. heart rate at parameters not deemed to be clinically Four active metabolites of vardenafil have been relevant. As PDE5 is expressed in vascular smooth identified. The most prominent metabolite, M1, is muscle cells, vasodilation has been recognized as a vardenafil with its ethyl group removed at the potential and mechanism-related side effect of PDE5 piperazine ring. M1 is an effective PDE5 inhibitor, inhibitor therapy. The related adverse events of but with a potency four times less than that of its vasodilatation, like cutaneous flushing, headache, parent compound. The metabolite’s contribution to nasal congestion, and rhinitis, have been reported the overall efficacy of vardenafil has been estimated with vardenafil use, but it is not yet clear whether at approximately 7% (Table 2). headache is due to vasodilation and increased The pharmacodynamics and pharmacokinetics of blood flow.7 However, at standard doses applied a single oral dose of vardenafil, 10 mg or 20 mg, were to the treatment of ED, these effects have not studied in 21 patients with erectile dysfunction (ED) been determined to produce clinically significant in a RigiScan study.6 Compared to placebo, varde- changes.5 nafil 10 mg led to a mean increase of 24.4 min in the Nitrates and nitrate donor compounds release NO, duration of 460% penile rigidity at the base, and of which stimulates guanylyl cyclase and by doing so 24.8 min at the tip. For the 20 mg dose, increases in enhances the synthesis of cGMP. Consequently, this class of coronary vasodilators is expected to amplify the pharmacodynamic effects of PDE5 inhibition Table 1 Comparison of pharmacokinetics of sildenafil, tadalafil, in all tissues and cells that express PDE5. This and vardenafil includes the risk of precipitous hypotension. There- fore, concomitant use of nitrate-containing prepara- Parameter Sildenafil Tadalafil Vardenafil tions is contraindicated with PDE5 inhibitor therapy. Although PDE5 is expressed to some extent 100 mga 20 mgb 20 mgc in human platelets, sildenafil alone exerts no direct Tmax (h) 1.1670.99 2.0 0.66 (0.250–3.0) T1/2 (h) 3.8270.84 17.5 3.971.31 effect on platelet function, but in vitro potentiates 7 7 8–9 Cmax (ng/ml) 327 236 378 20.9 1.83 the antiaggregatory effects of nitric oxide donors. AUC (ng Â h/ml) 19637859 8066 74.571.82 PDE5 is expressed not only in vascular tissue but also in the esophagus and in smooth muscle cells of Tmax indicates times of occurrence for maximum drug concentra- the intestine. Mechanisms dependent on nitric tion; T1/2 indicates half-life time of drug; Cmax indicates maximum concentration of drug. oxide–cGMP regulate the motility of the esophagus a Viagra product monograph. and pylorus. Consequently, dyspepsia and other b B Pullman, 1C351 (Cialis) Symposium, Indianapolis, IN, USA, digestive system disorders have been identified as June 7, 2001. mechanism-related side effects of PDE5 inhibitor c Klotz et al.5 therapy. As high concentrations of PDE5 are found in various regions of the brain, effects on cognitive and neurologic function have also been associated with Table 2 Relative potency (Prel) and overall potency (Poverall)of vardenafil and its metabolites PDE5 inhibitors. Growing experimental evidence in various animal models suggests that orally delivered Compound IC50 (nM) Prel (%) Poverall (%) sildenafil or vardenafil improved object recognition memory in rats.10 When administered before or Vardenafil 0.89 100 100 immediately following training, sildenafil facilitated BAY 44-5576 ¼ M1 3.2 27.8 7.2 BAY 44-5578 ¼ M4 16 5.6 0.06 retention performance of a one-trial step-through BAY 44-5577 ¼ M5 18 4.9 0.61 inhibitor avoidance task in both male and female mice.11 Sildenafil may affect retention by altering

Prel(%) ¼ 100 (%) Â IC50 (vardenafil)/IC50 (metabolite); Poverall mechanisms involved in memory storage, possibly (%) ¼ Prel (%) Â ratio AUC (%)/100 (%). through the nitric oxide-guanylyl cyclase-cGMP

International Journal of Impotence Research Vardenafil: Preclinical data E Bischoff S36 system.10 As yet, the effect of PDE5 inhibitors on system by PDE5 inhibitors? The NO-dependent cognition in humans has not been determined. In increase of intracellular cGMP by PDE5 inhibition a double-blind study of central side effects of has been shown to be an effective mechanism in sildenafil on attention and memory functions in the treatment of ED. Patients suffering from spinal young male subjects, the drug did not overtly affect cord injury lack the centrally mediated stimula- behavioral patterns.12 However, auditory event- tion of erectile nerves, which normally leads to a related brain potentials indicated an enhanced release of NO and subsequently to an increased ability to focus attention and to select relevant target synthesis of cGMP. That might explain the lower stimuli. efficacy of PDE5 inhibitors in this group of The nitric oxide–cGMP pathway is thought to be patients. Direct, NO-independent stimulation of involved in nociception, and evidence exists that soluble guanylyl cyclase (sGC) should also lead to PDE inhibitors can modulate the process of pain elevated cGMP levels in tissues and could be an perception. Nitric oxide substantially influences the attractive alternative therapeutic option for the resting activity of dorsal-horn neurons. In rats, treatment of ED in these patients. The use of PDE5 blockade of nitric oxide synthesis increased the inhibitors, which are able to chemically release frequency of background activity of high-threshold NO, may be a further option. mechanosensitive neurons and resulted in activity among 80% of previously inactive neurons.13 In- Another NO-independent treatment option could be hibition of NO synthesis did not significantly the inhibition of roh-kinase, which has been shown impact the background activity of non-nociceptive 19 to be effective in relaxation of penile tissue. The neurons. role of cGMP in spinal nociceptor transmision is In the formalin test in rats, sildenafil enhanced currently only poorly understood. Therefore, the the antinociceptive effect of diclofenac and pro- possibility of the modulation of this neuronal net- duced an antinociceptive effect itself during the work by PDE5 inhibitors is highly speculative and latter phase of the test.14 Furthermore, nitric oxide needs a lot of basic research. levels are known to increase in response to periph- eral nerve injury. While headache is one of the most common side effects of sildenafil therapy, this drug- related adverse event can more likely be attributed 15,16,17 to vasodilation than to elevated levels of NO. References Many uncertainties persist with respect to the interrelationships of pain, cGMP, and the physiolo- gic mechanisms of PDE inhibition. 1 Saenz de Tejada I et al. 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