Drug Interaction

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 1^st study and 12.5 mg in 2^nd
  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.