Ketoconazole kinetics in chronic peritoneal dialysis.

Area of Science:

• Pharmacokinetics
• Nephrology
• Clinical Pharmacy

Background:

• Patients with renal failure often require management of fungal infections.
• Peritoneal dialysis (PD) is a common treatment for end-stage renal disease.
• Understanding drug disposition in PD patients is crucial for effective and safe therapy.

Purpose of the Study:

• To investigate the pharmacokinetic profile of oral ketoconazole in patients with renal failure on PD.
• To determine ketoconazole serum and peritoneal fluid concentrations and clearance.
• To assess the impact of PD on ketoconazole protein binding.

Main Methods:

• Six patients with renal failure on PD received a 400 mg oral dose of ketoconazole.
• Serum and peritoneal fluid samples were collected to measure ketoconazole concentrations over time.
• Pharmacokinetic parameters including Cmax, Tmax, and t1/2 were calculated.
• Protein binding of ketoconazole in serum and peritoneal fluid was assessed.

Main Results:

• Maximum serum ketoconazole concentration (Cmax) was 2.3 +/- 1.7 microgram/ml at 3.3 +/- 1.6 hours.
• Serum half-life (t1/2) was 2.4 +/- 0.8 hours.
• Peritoneal clearance was minimal (<1 ml/min) with limited peritoneal penetration (3.4% of serum concentration at 5 hours).
• Ketoconazole exhibited significantly reduced serum protein binding in PD patients compared to healthy controls.
• Peritoneal fluid protein binding ranged from 50-80%, with unbound concentrations similar to therapeutic levels in healthy individuals.

Conclusions:

• Oral ketoconazole demonstrates limited peritoneal penetration and low clearance in patients undergoing PD.
• Altered protein binding in PD patients may influence ketoconazole's efficacy and safety.
• Therapeutic monitoring of unbound ketoconazole concentrations is recommended in this population.