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  • 1
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    Sildenafil citrate and blood-pressure–lowering drugs: results of drug interaction studies with an organic nitrate and a calcium antagonist
    Elsevier BV ; 1999
    In:  The American Journal of Cardiology Vol. 83, No. 5 ( 1999-03), p. 21-28
    Details
    In: The American Journal of Cardiology, Elsevier BV, Vol. 83, No. 5 ( 1999-03), p. 21-28
    Type of Medium: Online Resource
    ISSN: 0002-9149
    URL: Article
    DOI: 10.1016/S0002-9149(99)00044-2
    RVK:
    XA 18500
    Language: English
    Publisher: Elsevier BV
    Publication Date: 1999
    detail.hit.zdb_id: 2019595-3
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  • 2
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    Assessment of the pharmacokinetics, safety and tolerability of maraviroc, a novel CCR5 antagonist, in healthy volunteers
    Wiley ; 2008
    In:  British Journal of Clinical Pharmacology Vol. 65, No. s1 ( 2008-04), p. 5-18
    Details
    In: British Journal of Clinical Pharmacology, Wiley, Vol. 65, No. s1 ( 2008-04), p. 5-18
    Abstract: To evaluate the pharmacokinetics, safety and tolerability of single and multiple oral doses of maraviroc in healthy volunteers. METHODS Three double‐blind, placebo‐controlled, dose‐escalation studies with either single or multiple doses of maraviroc were conducted in healthy volunteers. Plasma and urine samples were collected to investigate the pharmacokinetics of maraviroc and evaluate any changes with respect to dose and duration/frequency of dosing. Safety and toleration of maraviroc were also assessed. RESULTS Maraviroc is rapidly absorbed following oral administration, and plasma T max is achieved within 0.5–4.0 h postdose. Steady‐state plasma concentrations are achieved after 7 consecutive days of dosing. Although the pharmacokinetics of maraviroc is nonproportional over the dose range studied (3–1200 mg), the degree of nonproportionality is small at clinically relevant doses. Renal clearance is approximately 10–12 l h −1 and appears unaffected by increasing maraviroc doses. Maraviroc does not significantly modulate the activity of CYP2D6 or CYP3A4 at clinically relevant doses. There were no serious adverse events in any of these studies, and doses up to 900 mg were generally well tolerated, with postural hypotension being the dose‐limiting event. There was no pattern or dose relationship observed with maraviroc with regard to laboratory abnormalities, including hepatic transaminases. No clinically significant increases in QTc were noted at clinically relevant doses. CONCLUSIONS Maraviroc is absorbed into the systemic circulation and reaches steady state by day 7 of multiple dosing. It does not significantly influence the activity of major drug‐metabolizing enzymes and is well tolerated at clinically relevant doses, with most adverse events being mild or moderate.
    Type of Medium: Online Resource
    ISSN: 0306-5251 , 1365-2125
    URL: Issue
    URL: Article
    DOI: 10.1111/bcp.2008.65.issue-s1
    DOI: 10.1111/j.1365-2125.2008.03130.x
    RVK:
    XA 33650
    Language: English
    Publisher: Wiley
    Publication Date: 2008
    detail.hit.zdb_id: 1498142-7
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  • 3
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    Pharmacokinetics of sildenafil after single oral doses in healthy male subjects: absolute bioavailability, food effects and dose proportionality
    Wiley ; 2002
    In:  British Journal of Clinical Pharmacology Vol. 53, No. s1 ( 2002-02)
    Details
    In: British Journal of Clinical Pharmacology, Wiley, Vol. 53, No. s1 ( 2002-02)
    Abstract: Aims  To determine the absolute bioavailability, dose proportionality and the effects of food on the pharmacokinetics of single oral doses of sildenafil citrate. Methods  Three open‐label, randomized crossover studies were conducted in healthy male subjects. Absolute bioavailability was determined by comparing pharmacokinetic data after administration of single oral and intravenous 50‐mg doses of sildenafil ( n =12 subjects). Food effects were examined by comparing pharmacokinetic data for sildenafil and its primary circulating metabolite, UK‐103,320, after administration of a single oral 100‐mg dose in the fasted and fed states ( n =34 subjects). Dose proportionality was assessed from pharmacokinetic data obtained after administration of four single oral doses of sildenafil (25, 50, 100 and 200 mg) to 32 subjects. The safety and tolerability of sildenafil were also assessed in all of these studies. Results  The calculated absolute oral bioavailability of sildenafil was 41% (90% CI: 36–47). Food slowed the rate of absorption, delaying mean t max by approximately 1 h and reducing C max by 29% (90% CI: 19–38). Systemic exposure, as assessed by the mean area under the plasma concentration–time curve (AUC), was reduced by 11% (90% CI: 6–16). These food effects were not considered to be of clinical significance. There was statistical evidence of nonproportionality in C max and AUC over the dose range 25–200 mg. However the degree of nonproportionality was small, with predicted increases in C max and AUC of 2.2‐ and 2.1‐fold, respectively, for a doubling in dose, and was thought to be clinically nonsignificant. Sildenafil was well tolerated in the three studies; the majority of adverse events were mild and transient. Conclusions  Sildenafil had a mean absolute bioavailability of 41%. Food caused small reductions in the rate and extent of systemic exposure; these reductions are unlikely to be of clinical significance. Across the dose range of 25–200 mg, systemic exposure increased in a slightly greater than dose‐proportional manner.
    Type of Medium: Online Resource
    ISSN: 0306-5251 , 1365-2125
    URL: Article
    DOI: 10.1046/j.0306-5251.2001.00027.x
    RVK:
    XA 33650
    Language: English
    Publisher: Wiley
    Publication Date: 2002
    detail.hit.zdb_id: 1498142-7
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  • 4
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    Sildenafil citrate potentiates the hypotensive effects of nitric oxide donor drugs in male patients with stable angina
    Elsevier BV ; 2000
    In:  Journal of the American College of Cardiology Vol. 36, No. 1 ( 2000-07), p. 25-31
    Details
    In: Journal of the American College of Cardiology, Elsevier BV, Vol. 36, No. 1 ( 2000-07), p. 25-31
    Type of Medium: Online Resource
    ISSN: 0735-1097
    URL: Article
    DOI: 10.1016/S0735-1097(00)00705-1
    RVK:
    XA 17760
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2000
    detail.hit.zdb_id: 1468327-1
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  • 5
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    Comparative human pharmacokinetics and metabolism of single‐dose oral and intravenous sildenafil
    Wiley ; 2002
    In:  British Journal of Clinical Pharmacology Vol. 53, No. s1 ( 2002-02)
    Details
    In: British Journal of Clinical Pharmacology, Wiley, Vol. 53, No. s1 ( 2002-02)
    Abstract: Aims  To characterize the absorption, metabolism and excretion of an oral and intravenous (IV) dose of radiolabelled [ 14 C]‐sildenafil citrate in healthy male subjects. Specific objectives were to measure the cumulative amount of drug‐related radiolabelled material excreted in the urine and faeces to characterize urinary and faecal radioactivity as unchanged sildenafil or its metabolites, and to quantify blood and plasma total radioactivity and unchanged drug concentrations. Methods  Six healthy male subjects between the ages of 45 and 58 years were enrolled in an open‐label, parallel‐group study; three subjects received the oral dose and three received the IV dose. Oral drug was administered as a single dose of 50‐mg [ 14 C]‐sildenafil, and IV drug was administered as a single dose of 25‐mg [ 14 C]‐sildenafil infused over 25 min. Each dosage form contained 50 µCi of radioactivity. For radioactivity assays, whole blood, plasma, urine and faeces samples were taken predose and at specified intervals up to 5 days postdose. Plasma samples were assayed for sildenafil and the metabolites UK‐103,320 and UK‐150,564. Metabolite profiling was also performed in plasma, faeces and urine. Results  Absorption of sildenafil after oral administration was rapid and approximately 92% whilst the absolute bioavailability was limited to 38%, due to first‐pass metabolism. Mean AUC t values showed that sildenafil accounted for about 60% of the total circulating radioactivity in the plasma after IV administration and for 32% after oral administration. Concentrations of radioactivity in whole blood were lower than in plasma, indicating limited penetration of sildenafil into blood cells. No unchanged sildenafil was detected in either urine or faeces, demonstrating that metabolism was the major mechanism of drug clearance. The principal routes of metabolism were N ‐demethylation, oxidation and aliphatic dehydroxylation. Sildenafil was well tolerated, with treatment‐related adverse events reported by three subjects. Two of these were mild, and there was one case of moderate leg pain. Conclusions  The pharmacokinetics of radiolabelled [ 14 C]‐sildenafil were consistent with rapid absorption, first‐pass metabolism and primarily faecal elimination of N ‐demethylated metabolites.
    Type of Medium: Online Resource
    ISSN: 0306-5251 , 1365-2125
    URL: Article
    DOI: 10.1046/j.06-5251.2001.00028.x
    RVK:
    XA 33650
    Language: English
    Publisher: Wiley
    Publication Date: 2002
    detail.hit.zdb_id: 1498142-7
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  • 6
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    Effects of CYP3A4 inhibitors on the pharmacokinetics of maraviroc in healthy volunteers
    Wiley ; 2008
    In:  British Journal of Clinical Pharmacology Vol. 65, No. s1 ( 2008-04), p. 27-37
    Details
    In: British Journal of Clinical Pharmacology, Wiley, Vol. 65, No. s1 ( 2008-04), p. 27-37
    Abstract: To evaluate the influence of cytochrome P450 (CYP) 3A4 inhibitors on the clinical pharmacokinetics of maraviroc, a novel CCR5 antagonist. METHODS Four open‐label, randomized, placebo‐controlled studies were conducted in healthy subjects to assess the effect of separate and distinct combinations of CYP3A4 inhibitors on the steady‐state pharmacokinetics of maraviroc. Study 1 was a two‐way crossover study investigating the influence of saquinavir (SQV; 1200 mg t.i.d.) and ketoconazole (400 mg q.d.) on the pharmacokinetics of maraviroc (100 mg b.i.d.). All subjects received maraviroc for 7 days in both study periods. Cohort 1 subjects also received SQV or placebo and cohort 2 subjects also received ketoconazole or placebo. Study 2 was a parallel‐group study including four treatment groups investigating the effects of ritonavir‐boosted lopinavir (LPV/r; 400 mg/100 mg b.i.d.), ritonavir‐boosted saquinavir (SQV/r; 1000 mg/100 mg b.i.d.), and low‐dose ritonavir (RTV; 100 mg b.i.d.) on the steady‐state pharmacokinetics of maraviroc (100 mg b.i.d.), and exploring whether maraviroc dose adjustment can compensate for interaction effects. Treatment lasted 28 days and comprised three distinct phases: (i) maraviroc alone on days 1–7; (ii) maraviroc + interactant on days 8–21; and (iii) maraviroc (adjusted dose) + interactant on days 22–28. Study 3 was a two‐way crossover study investigating the effects of atazanavir (ATZ; 400 mg q.d.) and ritonavir‐boosted atazanavir (ATZ/r; 300 mg/100 mg b.i.d.) on the pharmacokinetics of maraviroc (300 mg b.i.d.). All subjects received maraviroc on days 1–14 of both study periods. Subjects also received ATZ on days 1–7 and ATZ/r on days 8–14 of one treatment period, and placebo on days 1–14 of the other treatment period. Study 4 was a two‐way crossover study investigating the effects of ritonavir‐boosted tipranavir (TPV/r; 500 mg/200 mg b.i.d.) on the pharmacokinetics of maraviroc (150 mg b.i.d.). Subjects received maraviroc plus TPV/r or placebo on days 1–8. RESULTS All of the drugs/drug combinations tested (except for TPV/r) increased maraviroc exposure, albeit to different degrees of magnitude. SQV/r caused the largest increase in maraviroc exposure (8.3‐fold increase in AUC τ ), whereas RTV caused the smallest increase in maraviroc exposure (2.6‐fold increase in AUC τ ). Downward adjustment of the maraviroc dose in study 2 during co‐administration of HIV protease inhibitors was able to compensate for the interactions. TPV/r had no clinically relevant effect on maraviroc exposure at steady state. There were no treatment‐related serious adverse events or discontinuations due to adverse events in any of the studies, and most adverse events were mild or moderate in severity and resolved without intervention. CONCLUSIONS Potent CYP3A4 inhibitors, including ketoconazole and protease inhibitors (except TPV/r), increase maraviroc exposure. Downward adjustment of the maraviroc dose during co‐administration with protease inhibitors can compensate for the interaction. TPV/r does not affect the steady‐state pharmacokinetics of maraviroc, and hence no dose adjustment would be warranted.
    Type of Medium: Online Resource
    ISSN: 0306-5251 , 1365-2125
    URL: Issue
    URL: Article
    DOI: 10.1111/bcp.2008.65.issue-s1
    DOI: 10.1111/j.1365-2125.2008.03133.x
    RVK:
    XA 33650
    Language: English
    Publisher: Wiley
    Publication Date: 2008
    detail.hit.zdb_id: 1498142-7
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  • 7
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    Introduction
    Wiley ; 2002
    In:  British Journal of Clinical Pharmacology Vol. 53, No. s1 ( 2002-02)
    Details
    In: British Journal of Clinical Pharmacology, Wiley, Vol. 53, No. s1 ( 2002-02)
    Type of Medium: Online Resource
    ISSN: 0306-5251 , 1365-2125
    URL: Article
    DOI: 10.1046/j.0306-5251.2001.00026.x
    RVK:
    XA 33650
    Language: English
    Publisher: Wiley
    Publication Date: 2002
    detail.hit.zdb_id: 1498142-7
    SSG: 15,3
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  • 8
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    The effects of sildenafil on human sperm function in healthy volunteers
    Wiley ; 2002
    In:  British Journal of Clinical Pharmacology Vol. 53, No. s1 ( 2002-02)
    Details
    In: British Journal of Clinical Pharmacology, Wiley, Vol. 53, No. s1 ( 2002-02)
    Abstract: Aims  This double‐blind, randomized, four‐period, two‐way crossover study was conducted to evaluate the acute effects of oral sildenafil (100‐mg single dose) on sperm motility, count, density, morphology and vitality as well as ejaculate volume and viscosity in healthy male subjects. The concentrations of sildenafil and its primary circulating metabolite UK‐103,320 were measured in ejaculate and compared with those in plasma. The study also included assessments of safety and tolerability. Methods  A total of 17 healthy male volunteers aged 19–34 years were randomized to receive a single 100‐mg dose of sildenafil for two periods and a single dose of placebo for two periods, with each period separated by a minimum of 5–7 days. Sperm and ejaculate properties were evaluated from semen samples taken at screening and 1.5 h after dose. An additional semen sample was collected 4 h after dose, and drug and metabolite concentrations were measured in this sample and the sample taken 1.5 h after dose for comparison with plasma concentrations. Blood samples were collected before each dose and 0.25, 0.5, 1, 2, 3, 4 and 6 h after dose for measurement of sildenafil and metabolite concentrations. Results  Sildenafil had no statistically significant effect on sperm motility, count or density; the percentage of abnormal sperm forms; or the percentage of living sperm. It also did not affect ejaculate volume or viscosity. All measures were within normal ranges. Sildenafil distributed into the semen rapidly, resulting in significant correlations between concentrations of sildenafil in the semen and total ( R 2 =0.588) or free ( R 2 =0.454) plasma concentrations ( P 〈 0.0001). Total semen concentrations of sildenafil were 18% of total plasma concentrations. UK‐103,320 appeared to distribute more slowly from the plasma into the semen, resulting in a lack of correlation between semen and plasma concentrations. The amount of sildenafil and UK‐103,320 in the ejaculate was small ( 〈 2×10 −4 % of the administered dose at 1.5 h). Sildenafil was well tolerated; no patient withdrew from the study due to adverse events attributed to sildenafil. Conclusions  These results indicate that a single 100‐mg oral dose of sildenafil does not have an adverse effect on sperm function or ejaculate quality.
    Type of Medium: Online Resource
    ISSN: 0306-5251 , 1365-2125
    URL: Article
    DOI: 10.1046/j.0306-5251.2001.00033.x
    RVK:
    XA 33650
    Language: English
    Publisher: Wiley
    Publication Date: 2002
    detail.hit.zdb_id: 1498142-7
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  • 9
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    Pharmacokinetics, Safety, and Tolerability of Multiple Doses of the Novel Oxytocin Receptor Antagonist Cligosiban in Development for Premature Ejaculation: Two Randomized Clinical Trials in Healthy Subjects
    Oxford University Press (OUP) ; 2019
    In:  The Journal of Sexual Medicine Vol. 16, No. 2 ( 2019-02-01), p. 213-222
    Details
    In: The Journal of Sexual Medicine, Oxford University Press (OUP), Vol. 16, No. 2 ( 2019-02-01), p. 213-222
    Abstract: Cligosiban (formerly IX-01) is a selective oxytocin receptor antagonist being developed for the treatment of premature ejaculation (PE). Aim To investigate the plasma pharmacokinetics, safety, and tolerability of multiple oral doses of cligosiban in healthy male subjects; measure the amount of cligosiban in semen; and evaluate the potential of cligosiban to modulate CYP3A4. Methods Both studies were double-blind, placebo-controlled, parallel group designs involving sequential cohorts of 12 subjects each. Cligosiban dosage regimens were 100 mg, 400 mg, 800 mg, 1200 mg, 1,600 mg and 2,400 mg once daily for 10 days, administered as an aqueous dispersion. Outcomes Blood samplings for cligosiban assays and safety assessments were performed throughout both studies. Semen was collected on day 9 at 2–4 hours postdose in study 1 only. Safety assessments included monitoring of adverse events, 12-lead electrocardiography, vital signs, and laboratory safety assessments. Urine samples for assessment of the 6β-hydroxycortisol/cortisol ratio were collected before dosing on days 1 and 10. Results Cligosiban was rapidly absorbed after both single and multiple dosing, with maximum plasma concentrations typically measured at 1–3 hours postdose. The terminal half-life was approximately 12 hours, and steady state was achieved by day 3. Exposure increased approximately proportionally to dose after single dosing but less than proportionally after multiple dosing. Accumulation ratios were higher at the lower doses compared with higher doses (2.3 at 100 mg vs 1.1 at 2,400 mg). The mean amount of cligosiban in semen ranged from 0.22 to 2.01 μg over the 100–1,200 mg dose range ( & lt;0.0003% of the administered dose). There were no meaningful differences in the urinary 6β-hydroxycortisol/cortisol ratio after multiple dosing with cligosiban. Cligosiban appeared to be well tolerated at all dose levels. Clinical Implications Cligosiban is well tolerated following once-daily dosing over a wide dose range and does not appear to modulate CYP3A4 activity, suggesting limited potential for perpetrating drug–drug interactions via this mechanism. Strengths & Limitations The 2 controlled trials show good toleration and pharmacokinetic data, including negligible amounts of cligosiban in semen at doses expected to be therapeutic. Toleration of cligosiban will need to be confirmed in studies in patients with PE. Conclusion Cligosiban showed a good safety profile at doses predicted to be therapeutic or supratherapeutic along with a pharmacokinetic profile appropriate for as-required or once-daily dosing. There was no evidence that cligosiban inhibited or induced CYP3A4 at doses up to 2,400 mg.
    Type of Medium: Online Resource
    ISSN: 1743-6109 , 1743-6095
    URL: Article
    DOI: 10.1016/j.jsxm.2018.11.012
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2019
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  • 10
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    The effects of cotrimoxazole or tenofovir co‐administration on the pharmacokinetics of maraviroc in healthy volunteers
    Wiley ; 2008
    In:  British Journal of Clinical Pharmacology Vol. 65, No. s1 ( 2008-04), p. 47-53
    Details
    In: British Journal of Clinical Pharmacology, Wiley, Vol. 65, No. s1 ( 2008-04), p. 47-53
    Abstract: To assess the potential of cotrimoxazole and tenofovir, drugs which are inhibitors and/or substrates of renal transporters, to alter the pharmacokinetic profile of maraviroc. METHODS Two randomized, placebo‐controlled, two‐way crossover studies were conducted in healthy male and female subjects. In study 1, 16 subjects, aged 18–45 years, received maraviroc (300 mg b.i.d.) with and without cotrimoxazole (960 mg b.i.d.; 160 mg trimethoprim and 800 mg sulfamethoxazole). In study 2, 12 subjects, aged 21–45 years, received maraviroc (300 mg b.i.d.) with and without tenofovir (300 mg q.d.). For study 1, blood was collected predose and on days 1–7. In study 2, blood was collected predose, on day 1 and days 3–7. In both studies, blood was collected at intervals up to 12 h postdose on day 7. Urine was collected on day 7, 0–12 h post morning dose. Blood and urine were analysed for maraviroc using liquid chromatography/tandem mass spectrometry. RESULTS The geometric mean ratios for C max and AUC 12 were 119% and 111%, respectively, for maraviroc plus cotrimoxazole and 104% and 103%, respectively, for maraviroc plus tenofovir, compared with maraviroc plus placebo. Renal clearance of maraviroc plus placebo was 8.3 l h −1 and 8.5 l h −1 and was 7.8 l h −1 for maraviroc plus cotrimoxazole and maraviroc plus tenofovir. There were no serious or severe adverse events or any clinically significant changes in laboratory tests, blood pressure, or electrocardiograms. CONCLUSIONS Neither cotrimoxazole nor tenofovir caused a clinically significant effect on the pharmacokinetics of maraviroc. Maraviroc 300 mg b.i.d. was well tolerated when co‐administered with either cotrimoxazole or tenofovir.
    Type of Medium: Online Resource
    ISSN: 0306-5251 , 1365-2125
    URL: Issue
    URL: Article
    DOI: 10.1111/bcp.2008.65.issue-s1
    DOI: 10.1111/j.1365-2125.2008.03135.x
    RVK:
    XA 33650
    Language: English
    Publisher: Wiley
    Publication Date: 2008
    detail.hit.zdb_id: 1498142-7
    SSG: 15,3
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