|Year : 2013 | Volume
| Issue : 4 | Page : 330-333
Pharmacokinetics of single-dose primaquine in patients with chronic kidney dysfunction
Shaunak P Kulkarni1, Sanjana R Shah1, Prashant P Kadam1, Kannan Sridharan1, Nivrutti K Hase2, Partha P Shetty2, Urmila M Thatte1, Nithya J Gogtay1
1 Department of Pharmacology, Seth GS Medical College and KEM Hospital, Parel, Mumbai, India
2 Department of Nephrology, Seth GS Medical College and KEM Hospital, Parel, Mumbai, India
|Date of Submission||30-Nov-2012|
|Date of Decision||17-Feb-2013|
|Date of Acceptance||23-Apr-2013|
|Date of Web Publication||15-Jul-2013|
Nithya J Gogtay
Department of Pharmacology, Seth GS Medical College and KEM Hospital, Parel, Mumbai
Source of Support: None, Conflict of Interest: None
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 C max [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 t max [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.
Keywords: Antimalarials, chronic kidney disease, renal failure, special populations
|How to cite this article:|
Kulkarni SP, Shah SR, Kadam PP, Sridharan K, Hase NK, Shetty PP, Thatte UM, Gogtay NJ. Pharmacokinetics of single-dose primaquine in patients with chronic kidney dysfunction. Indian J Pharmacol 2013;45:330-3
|How to cite this URL:|
Kulkarni SP, Shah SR, Kadam PP, Sridharan K, Hase NK, Shetty PP, Thatte UM, Gogtay NJ. Pharmacokinetics of single-dose primaquine in patients with chronic kidney dysfunction. Indian J Pharmacol [serial online] 2013 [cited 2023 Mar 25];45:330-3. Available from: https://www.ijp-online.com/text.asp?2013/45/4/330/114997
| » Introduction|| |
Malaria, an important protozoal infectious disease in man, is estimated to affect around 225 million patients and caused 781,000 deaths worldwide in 2010.  Among the several Plasmodium species that cause malaria, Plasmodium falciparum and Plasmodium vivax cause most infections.
Primaquine, an 8-aminoquinoline, approved by United States Food and Drug Administration (US FDA) in 1952, is the only antimalarial drug active against hypnozoites (dormant liver stage) of P. vivax and Plasmodium ovale till date. Primaquine is currently recommended as an anti relapse medication for P. vivax infection (15 mg/day for 14 days) and for its gametocidal activity in P. falciparum infection (45 mg single dose). ,
Although the drug is in the market for over 60 years, there is a dearth of published data related to its pharmacokinetics in special populations. As the drug has not been subjected to a rigorous drug development process the prescription of Primaquine remains empirical in such populations.
Although Primaquine is extensively metabolized in the liver and only 0.5 to 2.4% of the parent compound is excreted unchanged in the urine,  renal dysfunction may still affect its pharmacokinetics.  The drug preferentially binds to the acute phase reactant protein alpha-1-acid glycoprotein (AAG),  which is elevated in patients with uremia as well as during hemodialysis.  Furthermore, animal models of chronic kidney disease (CKD) have shown inhibition of intestinal P-glycoprotein (an efflux transporter),  for which Primaquine is a substrate as well as an inhibitor.  Hence, this study was envisaged to evaluate the pharmacokinetics of a single dose (15 mg) Primaquine in patients with severe renal impairment and end-stage renal disease (ESRD) and compare them with healthy participants.
| » Materials and Methods|| |
Patients and eligibility criteria:
The study was carried out after obtaining approval from the Institutional Review Board (IRB)-Committee for Academic Research Ethics (CARE), Seth GS Medical College and KEM Hospital, Mumbai, India, and was registered with the Clinical Trial Registry of India (CTRI/2010/091/000356 and CTRI/2011/06/001803). Written informed consent was taken from all participants prior to screening for eligibility. The study was conducted between June 2010 and August 2011 and adult patients with CKD of either gender aged between 18 and 60 years were recruited. Patients were diagnosed as CKD as per National Kidney Foundation - Kidney Disease Outcome Quality Initiative (NKF-KDOQI)  and only those who fulfilled the criteria for stage IV and V (not on dialysis) were recruited. The data on normal healthy participants, who were enrolled in a similar pharmacokinetic study with primaquine in our center during the same period as this study was conducted, was used as concurrent controls. Normal volunteers were adjudged healthy based on medical history, clinical examination and routine laboratory testing. In both the groups, patients with abnormal G6PD activity, hemoglobin less than 7 g/dl, history of recent blood loss/blood or blood product transfusion, history of anti-malarial drug intake in the past 1 month, hypersensitivity to primaquine or related drugs (e.g., iodoquinol) or those receiving potentially hemolytic drugs were excluded as were pregnant and lactating women.
Study design and drug administration
This was a prospective pharmacokinetic study. Eligible participants were admitted in the ward and were given a standardized breakfast following an overnight fast. Tablet Primaquine phosphate 15 mg (Batch number TB078, Bharat Parenterals, India) was administered orally under direct supervision with 200 ml water within 30 minutes and a mouth check was done. Liquids were restricted for 2 hours and food for 4 hours post dose. The CKD patients continued their prescribed medicines for their primary disease and all the participants were discharged after a day's admission.
Timing of blood samplings
Following the single dose 15 mg primaquine post breakfast, 5-ml heparinized blood samples were collected through an indwelling forearm vein catheter at 0 h (pre-dose) and 0.5, 1.0, 1.5, 2, 3, 4, 6, 8, 12, and 24 h post-dose. As Primaquine is light sensitive, all blood collections were done in a darkened room and plasma separated and stored at -20 0 C in amber colored vials pending analysis which was completed within 4 months of sample collection.
Plasma primaquine concentrations were determined by a reverse phase HPLC method using the modified method of Dua et al.  A volume of 0.5 ml, 25 μl of internal standard (phenacetin), and 1 ml of ammonia solution were mixed and vortexed for 2 min. The organic layer was separated following extraction with n-hexane-ethyl acetate (3.5:0.5) and centrifugation at 2000 rpm for 10 minutes. The samples were evaporated to dryness at 40°C under gentle stream of nitrogen and reconstituted with 100 μl of mobile phase for HPLC analysis. Bondapak C18 column (3-mm internal diameter and 30-cm length) was used. The mobile phase consisted of 64% distilled water, 21% acetonitrile, 14% methanol, and 1% 0.1M perchloric acid. Column effluent was monitored with a UV detector at 254nm. The limit of quantification of primaquine was 1 ng/ml. The assay showed linearity over the range of 1-3000 ng/ml. Intra- and inter-day coefficients of variation were below 15%. The method was validated according to the US-FDA Guidelines. All the procedures were carried under dark condition.
Non-compartmental (model independent) pharmacokinetic parameters were derived using PK Solutions version 2.0 software. Maximum plasma drug concentration (C max ) and time to achieve the maximum concentration (t max ) were estimated from the plasma drug concentration-time curve. The elimination rate constant (k e ) was calculated using log-linear regression analysis and the elimination half-life (t 1/2 ) was calculated from the ratio ln2/k e . The linear trapezoidal method was used to derive area under the drug concentration-time curve (AUC 24 ) and was extrapolated to infinity (AUC∞ ). The mean residence time (MRT) was calculated as the ratio of AUMC to AUC. Oral clearance (CL/F) was expressed as a function of bioavailability (F) and calculated as dose/AUC∞ . Apparent volume of distribution (V/F) was calculated by the formula (CL/F)/k e .
Numerical data is expressed as median (range). The data was tested for normality using Kolmogorov-Smirnov test and Kruskal-Wallis H test with post-hoc Dunn's test was used to compare the pharmacokinetic data. Analysis was performed using GraphPad InStat version 3.05 for Windows 95, GraphPad Software, San Diego, California, USA, www.graphpad.com. A P-value of < 0.05 was considered significant. No formal sample size calculation was performed.
| » Results|| |
Demographic details and concomitant medications
A total of 12 participants were recruited in each group. [Table 1] summarizes the age, gender distribution, and body mass index in the groups.
|Table 1: Demographic details of the study patients administered primaquine|
Click here to view
The CKD patients received one or more of the following concomitant medications: sodium bicarbonate, amlodipine, nifedipine, atenolol, folic acid, furosemide, vitamin B complex, nebivolol, atorvastatin, aspirin, metformin, carvedilol, pregabalin, pentoxifylline, calcium, diltiazem, glimepiride, iron, prednisolone, erythropoietin, phosphorus, ranitidine, prazosin, none of which are known to interact significantly with primaquine.
A wide inter-individual variability was observed in all the pharmacokinetic parameters in both the healthy participants as well as the CKD patients. The C max [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 t max [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. A summary of the various pharmacokinetic parameters is shown in [Table 2]. The time-concentration (median) profile of the drug is depicted in [Figure 1].
|Figure 1: Time - Concentration (median) curve of healthy, stage IV and stage V CKD participants receiving primaquine|
Click here to view
|Table 2: Pharmacokinetic parameters for primaquine in median (range) for the study patients|
Click here to view
The drug was well tolerated and no adverse events were reported in the study participants.
| » Discussion|| |
The present study evaluated the pharmacokinetics of Primaquine following a single oral dose of 15 mg in 12 stage IV and 12 stage V (not on dialysis) patients compared to 12 normal healthy participants. Till date there are no published studies describing the pharmacokinetics of Primaquine in patients with renal dysfunction. We found that all the pharmacokinetic parameters in CKD patients were comparable to that of the healthy participants from our centre as well as to those reported from previous studies which were used as historical controls. , Furthermore, there was no difference between in the pharmacokinetics between stage IV and stage V CKD patients.
Primaquine is an ethnically insensitive, orally administered, almost completely (F = 0.96+0.08) and rapidly absorbed (t max 2+1 h) drug exhibiting first order (linear) kinetics (between 15 mg to 45 mg dose) with a large apparent volume of distribution (269+120 l). It is extensively metabolized by the liver to carboxy Primaquine. ,, Studies have shown that only 0.5 to 2.4% of the parent compound is excreted unchanged in the urine. ,, All these studies were performed in normal healthy volunteers except Bhatia et al. (in P. vivax malarial patients). 
Studies have shown that primaquine being a basic drug (pKa 10  ), preferentially binds to AAG,  which is elevated in renal failure especially.  It has been reported that the free drug concentrations (which are responsible for drug activity) of quinine (pKa of 8.4) and lignocaine (pKa of 7.9  ), both basic drugs like Primaquine are significantly decreased in patients with elevated AAG. , One of the limitations of our study is that we did not measure either the free plasma Primaquine concentration or AAG levels.
As renal excretion of unchanged primaquine is negligible, we performed the 'reduced PK study'  with severely impaired renal function as well as ESRD patients initially to see whether extreme reduction in the renal function would have effect on the pharmacokinetics of Primaquine. We observed no significant effects. The US-FDA recommends additional studies in mild and moderate states of renal dysfunction only if 50-100% (or lesser in case of drugs with narrow therapeutic index) increase in AUC is observed in patients with very poor renal function.  In our study we found only one patient with stage IV and two patients with stage V showing more than 50% elevation of AUC as compared to the healthy participants in this study as well as from previous studies ,, and patients with malaria.  It, therefore, does not seem necessary to do further single-dose pharmacokinetic studies in stages I to III of CKD.
In the present study, all the CKD patients had normal liver function tests. Elmes et al., and Cuong et al., have shown that the pharmacokinetics of primaquine is not different between men and women. Hence, we did not match the controls with age and sex. Primaquine is converted into three metabolites, the major of which is carboxy Primaquine and one earlier study has shown it to be undetectable in the urine at both the single dose and steady state. There is also lack of information on how this metabolite is eliminated from the body.  Both for this reason and cost of procuring the metabolite, the metabolite kinetics were not done. This remains a limitation of the study. Our study is also limited by a small sample size and no data on steady state pharmacokinetics. We can however conclude that the pharmacokinetics of primaquine does not appear to be altered in stages IV and V of CKD and therefore, a change in either dosage or frequency of administration may not be required in this population.
| » References|| |
|1.||World Malaria Report 2010. Available from: http://whqlibdoc.who.int/publications/2010/9789241564106_eng.pdf [Last accessed on 2012 Apr 12]. |
|2.||Hill DR, Baird KJ, Parise ME, Lewis LS, Ryan ET, Magill AJ. Primaquine: Report from CDC expert meeting on malaria chemoprophylaxis I. Am J Trop Med Hyg 2006;75:402-15. |
|3.||Burgoine KL, Bancone G, Nosten F. The reality of using Primaquine. Malar J 2010;9:376. |
|4.||Mihaly GW, Ward SA, Edwards G, Orme ML, Breckenridge AM. Pharmacokinetics of Primaquine in man: Identification of the carboxylic acid derivative as a major plasma metabolite. Br J Clin Pharmacol 1984;17:441-6. |
|5.||Fabre J, Balant L. Renal failure, drug pharmacokinetics and drug action. Clin Pharmacokinet 1976;1:99-120. |
|6.||Vinetz JM, Clain J, Bounkeua V, Eastman RT, Fidock D. Chemotherapy of Malaria. In: Brunton LL, Chabner BA, Knollmann BC, editors. Goodman and Gilman′s The Pharmacological Basis of Therapeutics. New York: McGraw-Hill; 2011. p. 1409. |
|7.||Vasson MP, Baguet JC, Arveiller MR, Bargnoux PJ, Giroud JP, Raichvarg D. Serum and urinary alpha-1 acid glycoprotein in chronic renal failure. Nephron 1993;65:299-303. |
|8.||Sun H, Frassetto L, Benet LZ. Effects of renal failure on drug transport and metabolism. Pharmacol Ther 2006;109:1-11. |
|9.||Hayeshi R, Masimirembwa C, Mukanganyama S, Ungell AL. The potential inhibitory effect of antiparasitic drugs and natural products on P-glycoprotein mediated efflux. Eur J Pharm Sci 2006;29:70-81. |
|10.||KDOQI Clinical Practice Guidelines for Chronic Kidney Disease: Evaluation, Classification, and Stratification. Available from: http://www.kidney.org/professionals/kdoqi/guidelines_ckd/p4_class_g1.htm [Last accessed on 2012 Apr 12]. |
|11.||Dua VK, Kar PK, Sarin R, Sharma VP. High performance liquid chromatographic determination of Primaquine and carboxyPrimaquine concentrations in plasma and blood cells in Plasmodium vivax malaria cases following chronic dosage with Primaquine. J Chromatogr B 1996;675:93-8. |
|12.||Mihaly GW, Ward SA, Edwards G, Nicholl DD, Orme ML, Breckendridge AM. Pharmacokinetics of Primaquine in man. I. Studies of the absolute bioavailability and effects of dose size. Br J Clin Pharmacol 1985;19:745-50. |
|13.||Greaves J, Evans DA, Gilles HM, Fletcher KA. Plasma kinetics and urinary excretion of Primaquine in man. Br J Clin Pharmacol 1980;10:399-405. |
|14.||Vale N, Moreira R, Gomes P. Primaquine revisited six decades after its discovery. Eur J Med Chem 2009;44:937-53. |
|15.||Ward SA, Mihaly GW, Edwards G, Looareesuwan S, Phillips RE, Chanthavanich P, et al. Pharmacokinetics of Primaquine in man II. Comparison of acute vs chronic dosage in Thai subjects. Br J Clin Pharmacol 1985;19:751-5. |
|16.||Nair A, Abrahamsson B, Barends DM, Groot DW, Kopp S, Polli JE, et al. Biowaiver monographs for immediate-release solid oral dosage forms: Primaquine phosphate. Am Pharm Assoc J Pharm Sci 2012;101:936-45. |
|17.||Fletcher KA, Evans DA, Gilles HM, Greaves J, Bunnag D, Harinasuta T. Studies on the pharmacokinetics of Primaquine. Bull World Health Organ 1981;59:407-12. |
|18.||Bhatia S, Saraph Y, Revankar S, Doshi J, Bharucha E, Desai N, et al. Pharmacokinetics of Primaquine in participants with P. vivax malaria. Eur J Clin Pharmacol 1986;31:205-10. |
|19.||Araujo MJ, Born J, Capela R, Casimiro C, Chambel P, Gomes P, et al. Imidazolidin-4-one derivatives of Primaquine as novel transmission-blocking antimalarials. J Med Chem 2005;48:888-92. |
|20.||Kanto J, Sellman R, Laurikainen E. Salivary concentrations of lignocaine in healthy volunteers. Br J Clin Pharmacol 1982;13:736-7. |
|21.||Roy L, Leblanc M, Bannon P, Villeneuve JP. Quinine pharmacokinetics in chronic haemodialysis patients. Br J Clin Pharmacol 2002;54:604-9. |
|22.||Routledge PA. The plasma protein binding of basic drugs. Br J Clin Pharmacol 1986;22:499-506. |
|23.||Pharmacokinetics in Patients with Impaired Renal Function - Study Design, Data Analysis, and Impact on Dosing and Labeling. Available from: http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM204959.pdf [Last accessed on 2012 Apr 15]. |
|24.||Elmes NJ, Bennett SM, Abdalla H, Carthew TL, Edstein MD. Short report: Lack of sex effect on the pharmacokinetics of primaquine. Am J Trop Med Hyg 2006;74:951-2. |
|25.||Cuong BT, Binh VQ, Dai B, Duy DN, Lovell CM, Rieckmann KH, et al. Does gender, food or grapefruit juice alter the pharmacokinetics of primaquine in healthy subjects? Br J Clin Pharmacol 2006;61:682-9. |
[Table 1], [Table 2]
|This article has been cited by|
||Drug interactions with antimalarial medications in older travelers: a clinical guide
| ||Jelena Lewis, Tania Gregorian, Ivan Portillo, Jeff Goad |
| ||Journal of Travel Medicine. 2020; 27(1) |
|[Pubmed] | [DOI]|