Population pharmacokinetics of primaquine and the effect of hepatic and renal dysfunction: An exploratory approach.

OBJECTIVES: We attempted to develop a population pharmacokinetic model for primaquine (PQ) and evaluate the effect of renal and hepatic dysfunction on PQ pharmacokinetics. MATERIALS AND METHODS: The data were collected from a prospective, nonrandomized clinical study in healthy volunteers and patients with mild-moderate hepatic dysfunction and renal dysfunction. Model development was conducted using NONMEM® software, and parameter estimation was conducted using first-order conditional estimation with interaction method. RESULTS: Final data included a total of 53 study participants (13 healthy individuals, 12 with mild hepatic dysfunction, 6 with moderate hepatic dysfunction, and 22 with renal dysfunction) with 458 concentrations records. Absorption rate constant (Ka) was constrained to be higher than elimination rate constant to avoid flip-flop situation. Mild hepatic dysfunction was a significant covariate on volume of distribution, and it is approximately three folds higher compared to other subjects. Fixed effects parameter estimates of the final model - absorption rate constant (Ka), volume of distribution (V), and clearance (CL) - were 0.95/h, 498 L, and 39 L/h, respectively. Between-subject variability estimates (% CV) on Ka, V, and CL were 77, 66, and 65, respectively. Residual error was modeled as combination error model with the parameter estimates for proportion error 12% CV and additive error (standard deviation) 1.5 ng/ml. CONCLUSION: Population pharmacokinetic modeling showed that the volume of distribution of PQ in subjects with moderate hepatic dysfunction increases approximately three folds resulting in a significantly lower plasma concentration.

Urinary enzymes in nephrotic syndrome.

Tubular damage is a complication associated with nephrotic syndrome and increased levels of urinary enzymes are of significant value in detection of the same. The aim of our study was to evaluate the use of urinary lysozyme and trehalase as markers of tubular dysfunction in nephrotic syndrome. This study assessed 35 nephrotic syndrome patients and 30 healthy controls matched for age and sex. Urine samples were examined at pretreatment and post treatment (8 weeks) stages for proteinuria, lysozyme and trehalase. At pretreatmant stage there was significant increase in urinary lysozyme and trehalase as compared to controls (p<0.001). A good correlation was observed between degree of proteinuria and urinary lysozyme (p<0.001;r=0.80) and trehalase (p<0.001; r=0.74). At the end of 8 weeks of treatment, the patients showed significant decrease in their urinary lysozyme and trehalase activity (p<0.001) but no correlation with degree of proteinuria was observed. Our results indicate that enzymes like lysozyme and trehalase can be used as markers of tubular dysfunction.

Pharmacokinetics of single-dose primaquine in patients with chronic kidney dysfunction.

AIM: The pharmacokinetics of primaquine has not been studied in special populations. Being a basic compound, preferential binding to alpha-1 acid glycoprotein and substrate for P-glycoprotein, may predispose the drug for an altered pharmacokinetics in states of renal dysfunction. This study attempts to evaluate the pharmacokinetics of a single oral dose (15 mg) of primaquine in severely impaired renal function and end stage renal dysfunction patients compared to healthy participants. MATERIALS AND METHODS: Twelve patients each with chronic kidney disease classified as either Stage IV or V (not on dialysis) were recruited. Data from 12 healthy participants was used as concurrent controls. Serial blood collections were performed following a single dose 15 mg Primaquine orally. Primaquine concentrations were measured in the plasma using a validated HPLC method. RESULTS: The Cmax [median (range) in ng/ml] was 29.3 (14.6-104.3), 40.3 (14.8 - 78.6), and 49.8 (15 - 169.6) and the tmax [median (range) in hours] was 3.0 (1.0- 6.0), 2.0 (1.5 - 8) and 2.0 (1.0 - 4.0) for healthy and stage IV, V (not on dialysis) CKD participants, respectively. No statistically significant difference was observed in any of the pharmacokinetic parameters between healthy, stage IV and V CKD participants. CONCLUSION: Pharmacokinetics of single oral dose primaquine (15 mg) does not appear to be altered in patients with severely impaired renal function and end stage renal dysfunction. A change in dose or frequency of the drug administration perhaps may not be required in this population.