As we all know about the popular saying ”health is wealth” – It says that Good health is the real wealth. In this world, the precious thing you can find out is “your health.” By taking this saying as a strong point, the researcher Gian Maria Pacifici from Università di Pisa, Associate Professor of Pharmacology from Italy review on the clinical pharmacology of primaquine, an important antimalarial drug, in adult subjects.
You know! Malaria affects about a quarter of a billion people and leads to almost 900,000 deaths annually. Plasmodium falciparum, Plasmodium vivax, Plasmodium ovale, Plasmodium malariae, and Plasmodium knowlesi are the malarial parasites that infect humans. Plasmodium falciparum and Plasmodium vivax cause most of the malarial infections worldwide and it is the most common and virulent parasite. Primaquine acts against primary and latent hepatic stages of Plasmodium parasites and is the only available drug for preventing relapses of Plasmodium vivax and Plasmodium ovale parasites. It is the only available antimalarial drug that eliminates the hypnozoite stage of Plasmodium parasites in the liver. It also displays gametocytocidal activity against Plasmodium falciparum and other Plasmodium parasites. However, primaquine is inactive against asexual blood stage parasites. It is an important antimalarial drug; however, its wider use has been restricted owing to its narrow therapeutic index. Primaquine is an important antimalarial drug. Primaquine is a safe drug, only 14 deaths have been reported in 200 million people treated with this drug. It may yield hemolytic toxicity in patients with deficient glucose-6-phosphate dehydrogenase activity and is commonly not given to these malarial patients. Primaquine may be converted to electrophilic intermediates that act as oxidation-reduction mediators. Such activity could contribute to antimalarial effects by generating reactive oxygen species or by interfering with mitochondrial electron transport in the parasite.
We can say that, Primaquine becomes increasingly important in malaria-endemic countries because it eliminates Plasmodium parasites. Although primaquine is widely recommended, it is commonly not given to malarial patients who have glucose-6-phosphate dehydrogenase deficient activity because of haemolytic toxicity. The toxicity of primaquine, in terms of hemolytic toxicity in subjects with glucose-6-phosphate dehydrogenase deficiency, was first described in Caucasians by Clayman and Negroes by Hockwald in 1952. WHO recommends a single oral dose of 0.25 mg/kg to block Plasmodium falciparum malaria transmission and confers a very low risk of haemolytic toxicity. Baird and Hoffman recommend an oral daily regimen of 0.5 mg/kg primaquine daily for 14 days to eliminate Plasmodium vivax and Plasmodium ovale parasites.
Let’s see what are the effects of Primaquine:
Gian Maria Pacifici says that a single oral dose of 45 mg primaquine base is effective in the elimination of gametocytes of the possibly chloroquine-resistant Plasmodium falciparum. The gametocyte counts decreased markedly within 3.5 days after the administration of primaquine showing a significant difference from the non-treated subjects in which mostly gametocytes still remain within 11.4 days. It can be used as gametocytocidal for Plasmodium falciparum if the drug is administered when matured gametocytes appeared in the peripheral blood. In areas of low malaria transmission, where symptomatic infections contribute substantially to malaria transmission, the use of gametocytocidal drugs reduces the incidence of malaria infections. Artemisinin resistance in Plasmodium falciparum lessens overall gametocytocidal activity, which provides a selective pressure to the spread of these resistant parasites. The addition of one dose of primaquine to artemisinins could help to counter the spread of artemisinin resistance. The antirelapse efficacy of a supervised 14-days of 15 mg oral daily primaquine therapy (N = 131) compared with no antirelapse therapy (N = 142) in 273 patients with confirmed Plasmodium vivax infection. There were 6/131 (4.6%) recurrences in patients treated with primaquine compared with 13/142 (9.2%) in those who did not receive primaquine. This treatment reduces the incidence of Plasmodium vivax gametocytes by 73%, which was comparable to the effect of primaquine on the incidence of blood-stage infection. In India, the standard treatment to prevent relapses of Plasmodium vivax malaria is a 5-day regimen of oral primaquine. However, between 1977 and 1997, the efficacy of this treatment declined from approximately 99% to 87%. The efficacy of a 5-day oral regimen was compared with the 14-day regimen currently recommended by the WHO. The relapse rates observed, over a 6-month period of follow-up, were 0% with a 14-day regimen, 26.7% with a 5-day regimen, and 11.7% in subjects who did not receive primaquine.
The researcher Gian Maria Pacifici from Università di Pisa said, Primaquine prevents malaria by attacking liver-stage parasites, a property distinguishing it from most chemoprophylactics. A daily adult regimen of 30 mg oral primaquine prevented malaria infection caused by Plasmodium falciparum and Plasmodium vivax for 20 weeks in 95 of 97 glucose-6-phosphate dehydrogenase normal subjects. In comparison, 37 of 149 (25%) subjects taking placebo in a parallel trial became parasitic. The protective efficacy of primaquine was 88% against Plasmodium falciparum and > 92% against Plasmodium vivax. Primaquine was as well tolerated as placebo. Good safety, tolerance, and efficacy, along with key advantages in dosing requirements, make primaquine an excellent drug for preventing malaria. Thai adult males (N = 85) with acute Plasmodium vivax infection were randomized to receive 30 mg or 60 mg oral daily primaquine for 7 days (N = 43 and 42, respectively). The regimens were well tolerated and all patients recovered fully. Median fever clearance time was 47 hours (range, 4 to 130 hours), mean+SD parasite clearance time was 87.7+25.3 hours. Gametocyte clearance and adverse effects were similar in the 2 groups. The recurrences comprised approximately 17% recrudescence and 12% relapses in a 30 mg oral daily primaquine group compared with 3% recrudescence and 4% relapses in a 60 mg daily group. These data suggest that the dose-response relationships for primaquine asexual stage and gametocytocidal activity in-vivo are different. A one-week course of primaquine 60 mg daily is an effective treatment against Plasmodium vivax infection.
Metabolism of primaquine:
The differential generation of CYP2D6 metabolites by racemic primaquine. The rate of metabolism of (+) -(S)-primaquine was significantly higher (50% depletion of 20 μM in 120 min) compared to (-) -(R)-primaquine (30% depletion) when incubated with CYP2D6. The estimated Vmax (μmol/min/mg) were 0.75, 0.98, and 0.42, with Km (μM) of 24.2, 33.1, and 21.6 for (+)-primaquine, (+)-primaquine, and (-)-primaquine, respectively. The metabolism of primaquine by human CYP2D6 and the generation of its metabolites display enantio-selectivity regarding the formation of hydroxylated products. This may partly explain by differential pharmacological and toxicological properties of primaquine enantiomers. The metabolism of primaquine using in-vitro recombinant metabolic enzymes from the cytochromes P450 (CYP) and mono-amine-oxidase (MAO) families. Relative activity factor (RAF)-weighted intrinsic clearance values showed the relative role of each enzyme MAO-A, CYPs 2C19, 3A4, and 2D6, with 76.1%, 17.0%, 5.2%, and 1.7% contributions to primaquine metabolites, respectively. MAO-A products derived from the primaquine aldehyde, a precursor to carboxy-primaquine. The result of this work shows that CYP2D6 and MAO-A are the key enzymes associated with primaquine metabolism. Differential metabolism of primaquine enantiomers by recombinant human CYP2D6 and mono-amine-oxidase (MAO A) was cryopreserved human hepatocytes in the presence/absence of chloroquine and quinine. Both chloroquine and quinine significantly inhibited the activity of CYP2D6. Primaquine depletion by MAO was not affected significantly by chloroquine and quinine. The activities of carboxy-primaquine and primaquine alcohol glucuronide were significantly suppressed by chloroquine and quinine. Chloroquine and quinine also inhibited the activity of m/z 257 metabolite with a similar pattern. The apparent quinone-imine of carboxy-primaquine (m/z 289) was only partially suppressed by both quinine and chloroquine, but with a differential pattern of inhibition of the two drugs. The m/z 274 (quinone-imine, a ring-hydroxylated primaquine metabolite) and m/z 422 (a glucose conjugate of primaquine) metabolites were strongly suppressed by both quinine and chloroquine in hepatocytes, perhaps a reflection of CYP2D6 inhibition by these drugs. The formation of carbamoyl of primaquine (m/z 480) was not affected by chloroquine and quinine. These results suggest a complex picture in which chloroquine and quinine may shift metabolite pathway balances. Alternatively, chloroquine and quinine may alter transport or distribution of primaquine metabolites in a fashion that reduces the toxicity while maintaining efficacy against the parasite. The only primaquine metabolite generated by CYP2D6 is carboxy-primaquine. Ketoconazole, a known inhibitor of CYP isozymes, caused marked inhibition of carboxy-primaquine formation with IC50 and K(i) values of 15 and 6.7 μM. This finding and the dependency of the metabolite formation by NADPH indicates that CYPs catalyzed the metabolite production. Of compounds actually or likely to be co-administered with primaquine to malaria patients, only mefloquine produced an inhibition (K(i) = 52.5 μM). Quinine, artemether, artesunate, halofantrine, and chloroquine did not significantly inhibit metabolite formation. It seems unlikely that the concurrent administration of mefloquine, or other antimalarial drugs, with primaquine, will lead to appreciably altered disposition.
Pharmacokinetics of primaquine:
The absorption of primaquine from the gastrointestinal tract approaches 100%. After a single oral dose of primaquine, the plasma concentration of this drug reaches a maximum within 3 hours and then falls with a variable elimination rate with a half-life averaging 7 hours. The 5 healthy male volunteers aged between 24 and 45 years, who were taking no other drugs. An oral dose of primaquine base of 45 mg was administered after an overnight fast. Venous blood samples were taken at time 0, and 0.5, 1, 2, 3, 4, 6, 8, 12, and 24 hours after primaquine administration. Urine was collected for 1-hour pre-dose and from 0 to 24 hours after treatment. The subject “RB” received a tracer dose of [14C]-primaquine (8.25 μCi, 2.4 mg) by mouth. In this volunteer, the plasma was collected over 120 hours and the urine collections were continued collected for 6 days. Plasma and urine samples were assayed for primaquine, carboxy-primaquine, and N-acetyl primaquine. The pharmacokinetic parameters of primaquine and carboxy-primaquine are as follows:
Ae(24) = amount excreted in the urine for 24 hours, *calculated using bioavailability of 0.74.
The pharmacokinetics of primaquine and its metabolite carboxy-primaquine in 30 male Korean patients infected by Plasmodium vivax. The patient age ranged from 21 to 24 years. The patients were treated with 1.5 g chloroquine base for 3 days and then received 15 mg primaquine daily by mouth for 14 days. The blood samples were collected at 1, 1.5, 2, 2.5, 3, 4, 12, and 24 hours after the first dose of primaquine. The plasma concentration of primaquine increased rapidly after the administration and Cmax reached 1.5 hours after administration. The plasma concentration of carboxy-primaquine reached a maximum of 0.319+0.126 μg/ml at 4 hours after the administration of primaquine and decreased slowly until 24 hours. A large variation in the plasma of both primaquine and carboxy-primaquine was observed in these patients. The pharmacokinetic parameters of both primaquine and carboxy-primaquine are as follows:
Both primaquine and carboxy-primaquine have antiplasmodial activity. Six Caucasians and 11 Thai male volunteers were treated with a single oral dose of 45 mg primaquine base, after overnight fasting. Five of the Thai volunteers were glucose-6-phosphate dehydrogenase deficient. Three male Thai volunteers were given a daily oral dose of 15 mg of primaquine base for 5 days following the administration of chloroquine (1.5 g free base) one week previously receiving primaquine. Blood samples were withdrawn at time 0, and 1, 2, 5, 4, 6, 9 and 24 hours after administration of primaquine. The regimen for multiple dosing was an oral dose of 15 mg primaquine base on each of 5 days associated with a dose of a chloroquine free base of 1.5 g, 1 week previously primaquine administration. This regimen was used therapeutically in Thailand and was conducted in three Thai volunteers. Blood samples were withdrawn at time 0, and 0.5, 1, 1.5, 2.5, 4, 6 and 9 hours on the final day of primaquine administration. The pharmacokinetic parameters after a single oral dose of 45 mg and the pharmacokinetic parameters of primaquine after multiple oral doses of 15 mg in three Tai subjects are as follows.
The pharmacokinetics of primaquine were studied in 6 Caucasians and 11 Thai male volunteers receiving an oral single dose of 45 mg of primaquine free base, after overnight fasting. Fasting was continued for a further three hours after primaquine administration. Urine was collected from the six Caucasians for 24 hours after treatment. Five of Thai volunteers were glucose-6-phosphate dehydrogenase deficient. Blood samples for the estimation of plasma primaquine levels were taken immediately before primaquine administration, and before the daily primaquine administration on days 7, 13, and 14. The pharmacokinetic parameters of primaquine are as follows:
G6PD = glucose-6-phosphate dehydrogenase, *bioavailability is assumed to be 1, **level of statistical significance between Thai subjects with normal and deficient glucose-6-phosphate-deydrogenase activity, Bartlett’s test for unpaired data.
Urine was collected over 24 hours period following the administration of primaquine. Three male Thai volunteers were given an oral dose of 15 mg primaquine base daily for 5 days, following the administration of chloroquine (1.5 g free base) one week previously primaquine administration. Several blood samples were taken after the last dose on day 5. The pharmacokinetic parameters of primaquine are as follows.
* Bioavailability is assumed to be 1.
The pharmacokinetics of primaquine were studied in 4 males and 4 females aged between 22 and 29 years weighing 43 to 65 kg. They were taking no other drugs. All subjects were found to be healthy and had normal laboratory findings. All of them received a daily oral dose of 15 mg of primaquine base after overnight fast and before breakfast for 14 consecutive days. Blood samples were taken pre-dose and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 18, and 24 hours after the first dose of primaquine, then daily before primaquine administration until day 13. After the last dose on day 13, blood samples were collected using the same schedule as the first 24 hours after the first dose of primaquine, and again at 30 and 40 hours after primaquine administration. The pharmacokinetic parameters of primaquine in plasma are as follows.
Cl/Bw = Clearance/body weight, *Level of statistical significance of primaquine pharmacokinetic parameter measured on the first and last days, Bartlett’s test for unpaired data.
Thirteen Tai subjects had normal glucose-6-phosphate dehydrogenase activity and 13 Tai subjects had glucose-6-phosphate dehydrogenase deficient activity. Glucose-6-phosphate dehydrogenase activity was checked on admission in all patients. Complete blood counts including reticulocyte counts, urinalysis, and blood biochemistry tests were done on admission and on days 2, 4, 7, and 14. Thai male patients infected with Plasmodium vivax, aged between 20 and 50 years, weight range 45-60 kg, with no liver or kidney diseases were taking antimalarials for this episode of illness were recruited. No other drugs were taken during the study. The patients were given oral chloroquine 1,5 g base over 3 days, followed by a daily oral dose of 15 mg primaquine for 14 days. The first dose of primaquine was started on the day after the last dose of chloroquine. Parasite counts were made every 12 hours after primaquine treatment until parasitaemia fell below the level of microscopical detection in a thick blood film. Physical examination and adverse effects during the study period were recorded once daily until discharged. After the first dose of primaquine, blood specimens were sampled for assay of primaquine levels and were collected at 2, 4, 8, 12, and 24 hours after primaquine administration, then before dosing on days 2, 3, 4, 6, 8, 12, and 14. The pharmacokinetic parameters of primaquine after a single oral dose of 15 mg primaquine to patients with Plasmodium vivax infection are as follows:
G6PD = glucose-6-phosphate dehydrogenase, AUC = area under the curve, clearance/f = oral clearance, Vz/f = apparent distribution volume, (f = fraction of the oral dose which reached the systemic circulation), *level of statistical significance between Thai patients with normal and deficient glucose-6-phosphate dehydrogenase activity, Bartlett’s test for unpaired data.
There was no difference in the plasma concentrations and pharmacokinetic parameters of primaquine in patients with normal and deficient glucose-6-phosphate dehydrogenase activities. In glucose-6-phosphate dehydrogenase deficient group, no relationship between the severity of haemolysis (< 20% or > 20% haemolysis) and the concentrations/pharmacokinetics of primaquine was observed.
The researcher Gian Maria Pacifici intention is to defend malaria with an effective drug called PRIMAQUINE. In her opinion, the review of research “Clinical pharmacology of the antimalarial primaquine in adult subjects” will surely impact us.
“Protect the health, then health will safeguard you.”