Speciality
Spotlight

 




           

Clinical Pharmacology

       

     





Drug Interactions

   

  • Gary J
    Muirhead, Maria B Wulff, et al (Early Clinical
    Research Group, Pfizer Central Research, Sandwich
    Kent, UK and Hoffmann-La Roche, Basel, Switzerland).




    Pharmacokinetic interactions between sildenafil
    and saquinavir/ritonavir





    Br.
    J.Clin.Pharmacol, vol.50(2), August 2000, p.99-107.


      


    Aim of the
    study was to investigate the effect of
    antiretroviral protease inhibitors saquinavir (soft
    gelatin capsules) and ritonavir on the
    pharmacokinetics and tolerability of sildenafil and
    also to investigate the effect of sildenafil on
    steady-state pharmacokinetics of saquinavir and
    ritonavir.




      

    Study was
    conducted in 28 healthy male volunteers. Both protease inhibitors significantly
    increased Cmax, AUC, Tmax and t.½ values for
    both sildenafil and UK-103, 320 (metabolite). Ritonavir showed a significantly greater
    effect than saquinavir with increases in sildenafil
    AUC and Cmax of 2 fold and 3.9 fold respectively. Steady-state pharmacokinetics of saquinavir
    and ritonavir were unaffected by sildenafil. There was no associated increased incidence
    of adverse events or clinically significant 
    changes in BP, heart-rate or ECG parameters.




      

    The results
    indicate that both saquinavir and ritonavir modify
    the pharmacokinetics of sildenafil, probably through
    inhibition of CYP3A4. More pronounced effect of ritonavir – due to
    additional potent inhibition of CYP2C9. A lower sildenafil starting dose (25mg)
    should be considered for patients receiving
    saquinavir and it is recommended not to exceed a
    maximum single dose of 25mg in a 48hr. period in
    patients receiving ritonavir.




      

    Editors
    commentary-by D.J.Back


     

     

    These data
    are consistent with a previous study which
    demonstrated that the AUC of sildenafil when given
    with the protease inhibitor indinavir was 4.4 fold
    greater than data from historical controls.




      

    Not all
    drug interactions reported in the literature are
    clinically relevant. This one has direct relevance to HIV infected
    men.  Prevalence
    of erectile dysfunction in this group has been
    reported as 33%, increasing with more advanced HIV
    disease. Many
    patients wish to avail themselves of sildenafil
    therapy.  Protease inhibitors, especially ritonavir, are potent
    inhibitors of CYP3A4 and other cytochrome P450 enzymes. It is surprising that in this study, there
    were no adverse effects on BP, heart rate or ECG. 
    In 2 other reported studies, adverse events
    were headache, facial flushing, dyspepsia and
    rhinitis – these 2 studies were conducted in
    HIV-infected patients.




      

    Authors are
    agreed that a low starting-dose of sildenafil (-
    25mg – in 1st study and 12.5 mg in 2nd
    study) is advisable in patients receiving
    concomitant protease inhibitors.




      

    Erythromycin
    and cimetidine produce similar effects. There are grounds to be cautious when
    sildenafil is used with a whole range of drugs.

       

  • Jean
    Frederic Westphal (Unit
    of Geriatric Medicine, France
    )

    Macrolide
    – induced clinically relevant drug interactions with
    cytochrome P-450a
    (cyp)
    3A4: an update focused on clarithromycin,
    azithromycin and dirithromycin.

    Br.
    Jr.Cl. Pharmacology, oct.2000, 50(4), 285-295

      

    Summary:
    Erythromycin binds strongly, clarithromycin to a
    lesser extent and azithromycin the least to the
    cytochrome CYP 3A4, which is involved in oxidative
    phase of biotransformation of drugs.
    Hence, erythromycin produces maximum drug
    interactions and azithromycin and dirithromycin the
    least drug interactions.

       

    Clinically
    relevant drug-interactions with benzodiazepines,
    neuroleptics, HMG CoA reductase inhibitors,
    anti-arrhythmic agents and warfarin are described.

        



  
 



 

     

Speciality Spotlight

 

           
Clinical Pharmacology
       

     

Drug Interactions
   

  • Gary J Muirhead, Maria B Wulff, et al (Early Clinical Research Group, Pfizer Central Research, Sandwich Kent, UK and Hoffmann-La Roche, Basel, Switzerland).


    Pharmacokinetic interactions between sildenafil and saquinavir/ritonavir


    Br. J.Clin.Pharmacol, vol.50(2), August 2000, p.99-107.
      
    Aim of the study was to investigate the effect of antiretroviral protease inhibitors saquinavir (soft gelatin capsules) and ritonavir on the pharmacokinetics and tolerability of sildenafil and also to investigate the effect of sildenafil on steady-state pharmacokinetics of saquinavir and ritonavir.


      
    Study was conducted in 28 healthy male volunteers. Both protease inhibitors significantly increased Cmax, AUC, Tmax and t.½ values for both sildenafil and UK-103, 320 (metabolite). Ritonavir showed a significantly greater effect than saquinavir with increases in sildenafil AUC and Cmax of 2 fold and 3.9 fold respectively. Steady-state pharmacokinetics of saquinavir and ritonavir were unaffected by sildenafil. There was no associated increased incidence of adverse events or clinically significant  changes in BP, heart-rate or ECG parameters.


      
    The results indicate that both saquinavir and ritonavir modify the pharmacokinetics of sildenafil, probably through inhibition of CYP3A4. More pronounced effect of ritonavir – due to additional potent inhibition of CYP2C9. A lower sildenafil starting dose (25mg) should be considered for patients receiving saquinavir and it is recommended not to exceed a maximum single dose of 25mg in a 48hr. period in patients receiving ritonavir.


      
    Editors commentary-by D.J.Back

     

     
    These data are consistent with a previous study which demonstrated that the AUC of sildenafil when given with the protease inhibitor indinavir was 4.4 fold greater than data from historical controls.


      
    Not all drug interactions reported in the literature are clinically relevant. This one has direct relevance to HIV infected men.  Prevalence of erectile dysfunction in this group has been reported as 33%, increasing with more advanced HIV disease. Many patients wish to avail themselves of sildenafil therapy.  Protease inhibitors, especially ritonavir, are potent inhibitors of CYP3A4 and other cytochrome P450 enzymes. It is surprising that in this study, there were no adverse effects on BP, heart rate or ECG.  In 2 other reported studies, adverse events were headache, facial flushing, dyspepsia and rhinitis – these 2 studies were conducted in HIV-infected patients.


      
    Authors are agreed that a low starting-dose of sildenafil (- 25mg – in 1st study and 12.5 mg in 2nd study) is advisable in patients receiving concomitant protease inhibitors.


      
    Erythromycin and cimetidine produce similar effects. There are grounds to be cautious when sildenafil is used with a whole range of drugs.
       

  • Jean Frederic Westphal (Unit of Geriatric Medicine, France)
    Macrolide – induced clinically relevant drug interactions with cytochrome P-450a (cyp) 3A4: an update focused on clarithromycin, azithromycin and dirithromycin.
    Br. Jr.Cl. Pharmacology, oct.2000, 50(4), 285-295
      
    Summary: Erythromycin binds strongly, clarithromycin to a lesser extent and azithromycin the least to the cytochrome CYP 3A4, which is involved in oxidative phase of biotransformation of drugs. Hence, erythromycin produces maximum drug interactions and azithromycin and dirithromycin the least drug interactions.
       
    Clinically relevant drug-interactions with benzodiazepines, neuroleptics, HMG CoA reductase inhibitors, anti-arrhythmic agents and warfarin are described.
        

    

 

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