PHILIP AGOP PHILIP, M.D., Ph.D., F.R.C.P. Baccalaureate, American Jesuit Fathers’ College, Baghdad, Iraq. M.D. Degree, University of Baghdad, College of Medicine, Baghdad, Iraq. Ph.D. in Clinical Pharmacology and Pharmacogenetics , University of London, Guy’s Hospital Medical School, London, UK. Intern in Internal Medicine and General Surgery, Medical City Teaching Hospital, University
American people can buy antibiotics in Australia online here: https://buyantibiotics-24h.com/ No prescription required and cheap price!
Sc.psu.ac.thJournal of Clinical Pharmacy and Therapeutics (2005) 30, 285–290 Ketoconazole increases plasma concentrationsof antimalarial mefloquine in healthy human volunteers W. Ridtitid MD FCFPT, M. Wongnawa MSc, W. Mahatthanatrakul MD FCFPT,N. Raungsri MSc and M. Sunbhanich PhDDepartment of Pharmacology, Faculty of Science, Prince of Songkla University, Hat Yai, Thailand mechanisms of the increase in plasma mefloquine concentrations may be the result of the inhibition of CYP3A4 by ketoconazole. In case of mefloqu- structure related to quinine. The major metabolite ine is co-administered with ketoconazole, drug– of quinine is 3-hydroxyquinine formed by cyto- drug interactions should be recognized and the chrome P450 3A4 (CYP3A4). Ketoconazole, a dose of mefloquine should be adjusted to max- potent inhibitor of CYP3A4, is known to mark- imize the therapeutic efficacy and to reduce the edly increase plasma concentrations of various co-administered drugs including quinine.
Objective: To assess the effect of ketoconazole Keywords: drug–drug interactions, ketoconazole, on plasma concentrations of mefloquine in heal- mefloquine, pharmacokinetics, plasma concen- Methods: In an open, randomized two-phasecrossover study separated by a 1-month period,eight healthy Thai male volunteers received a single oral dose of 500 mg mefloquine alone orco-administration with 400 mg/day ketoconazole Mefloquine [dl-erythro-a-(2-piperidyl)-2,8-bis (tri- orally for 10 days. Serial blood samples were fluoromethyl)-4-quinoline methanol] is a quino- collected at specific time points for a 56-day per- linemethanol antimalarial drug structurally related iod. Plasma mefloquine and mefloquine carb- to quinine. It is an effective single dose therapy for oxylic metabolite concentrations during 56 days all species of malarial parasites infecting humans, were measured by a modified and validated high- including multidrug-resistant Plasmodium falcipa- performance liquid chromatographic method rum. It is still used both in prophylaxis and treat- ment of the disease in most areas with multidrug- Results: Co-administration with ketoconazole resistant P. falciparum (1–3). Mefloquine is relat- markedly increased the mean values of mefloqu- ively well tolerated and has the advantage of a single daily dose regimen making it suitable for mefloquine alone by 79% (P < 0Æ001), 39% prophylactic use (4). However, mefloquine mono- (P < 0Æ05) and 64% (P < 0Æ001) respectively. The therapy for uncomplicated falciparum malaria was discontinued and replaced with a combination of 0)t , and Cmax of mefloquine carboxylic acid metabolite were decreased by 28% (P < 0Æ05) and mefloquine (25 mg/kg) and artesunate adminis- 31% (P < 0Æ05), respectively when compared with tration (4 mg/kg/day) (2, 5). Mefloquine is distri- buted extensively in tissues and eliminated slowly, Conclusions: Co-administration with ketoconaz- with considerable differences between individuals ole increased plasma mefloquine concentrations (2). Following the oral administration of a single in healthy human volunteers. One of possible 25 mg/kg dose of mefloquine to patients withacute falciparum, the mean values of Cl/f, Vd/f, Ke, Received 1 February 2005, Accepted 15 March 2005 t1/2 and AUC0)a of mefloquine were 0Æ733 L/kg/ Correspondence: Wibool Ridtitid, Department of Pharmacology,Faculty of Science, Prince of Songkla University, Hat Yai 90112, Thailand. Tel/fax: +66-74-446678; e-mail: firstname.lastname@example.org 34 106 ng/mL/day, respectively (6). After 1000 mg (divided into three doses over 12 h) mefloquine SGOT, SGPT, direct bilirubin and albumin/glob- administration orally in healthy White male, the ulin) were carried out in each volunteer. None of mean ± SD values of Cmax, Tmax, AUC0)846 h, volunteers was a smoker or used continuous AUC0)a and t1/2 were 1000 ± 266 ng/mL, 23 ± medications. Drinking of alcoholic beverages, cof- fee and tea were not allowed at least 1 month prior and 427 ± 198 h, respectively (7). Two mefloquine to and during the entire period of study. Written metabolites identified in humans are hydroxy and informed consent was received from each subject carboxylic acid metabolites. The main metabolite is prior to the study. The study protocol was 2,8-bis -trifluoromethyl-4-quinolinecarboxylic acid reviewed and approved by the Ethics Committee of and inactive for P. falciparum (8). Quinine is a the Faculty of Medicine, Prince of Songkla Uni- widely used antimalarial drug for the treatment of severe or multidrug-resistant P. falciparum (9, 10).
The CYP3A4 is a major cytocrome P450 involved in the metabolism of quinine both in vitro and in vivo(6, 11, 12).
The study was an open-label, two-phase cross- Ketoconazole, a broad spectrum azole anti- over design with a 1-month separation between mycotics, is a potent inhibitor of CYP3A4 resulting phases. A single oral dose of 500 mg mefloquine the significant increase in plasma concentrations of (MEQUINÒ, 250 mg/tablet, Lot No.010192; Atlan- various drugs co-administered, for example quin- tic Laboratories Corp. Ltd, Bangkok, Thailand) was ine (13). As ketoconazole is one of azole com- kindly donated by the Insect Prevention Center, pounds, a number of side-effects are associated with ketoconazole as a result of inhibition of thesemammalian enzymes (14). Ketoconazole leads to Phase 1. On the study day, four subjects ingested liver damage because of its ability to inhibit only 500 mg mefloquine with 200 mL water.
CYP3A4, the major P450 isoform of the liver (15).
Another four subjects received mefloquine plus The inhibition of CYP3A4 results in drug–drug 400 mg ketoconazole (KETAZOL, 200 mg/tablet, interactions involving ketoconazole and a decrease Lot No.1A918/31; Central Poly Trading Co. Ltd, in the rate of clearance of many drugs (16). Steroid Bangkok, Thailand). Each subject ingested 400 mg biosynthesis by P450 enzymes is also inhibited by ketoconazole once daily before breakfast for 5 days ketoconazole, presumably because of the binding prior to mefloquine administration and for a fur- of ketoconazole to the mitochondria P450 enzymes, and the administration of low doses of ketoconaz-ole leads to a significant reduction in serum and- Phase 2. The four subjects who ingested 500 mg mefloquine alone in phase 1 or treatment 1 Mefloquine has a structurally chemical related to were changed to have mefloquine plus ketoconaz- quinine. As quinine is extensively metabolized by ole, and another four subjects who ingested CYP3A4 to form 3-hydroxyquinine, a major meta- mefloquine plus ketoconazole in phase 1 or treat- bolite (6, 11, 12), therefore, ketoconazole would ment 1 were changed to have only mefloquine alone.
theoretically alter the metabolism of mefloquine.
All subjects fasted overnight before mefloquine administration and received a regular meal 3 h aftermefloquine. The subjects were not allowed to smoke or have coffee, tea, alcohol or cola on the test day.
Determination of plasma mefloquine and its Eight Thai male volunteers, age 16–39 years (mean age 29Æ5 ± 8Æ4 years) and weighed 56–64 kg (meanweight 61Æ5 ± 2Æ6 kg) participated in the study.
A forearm vein was inserted with a sterile intra- Prior to the study, a medical history, physical examination, standard biochemical and haemato- blood samples, maintained patent with 1 mL of a logical screening test (CBC, FBS, BUN, creatinine, dilute heparin solution (100 unit/mL) after each Ó 2005 Blackwell Publishing Ltd, Journal of Clinical Pharmacy and Therapeutics, 30, 285–290 Plasma concentrations of antimalarial mefloquine sampling. Serial venous blood samples (5 mL) were collected into heparinized tubes before drug administration and at 0, 0Æ5, 1, 2, 3, 4, 6, 8, 10, 12 h,and 2, 3, 4, 7, 14, 21, 35, 49 and 56 days post-drug Eight healthy volunteers were enrolled and com- administration. Samples were centrifuged not later pleted this study. No side-effects were observed than 30 min after collection, and the plasma was after taking 500 mg of mefloquine alone. However, separated and stored at )60 °C until analysis. The two subjects reported mild headache during plasma mefloquine (molecular weight 414Æ79) and ketoconazole co-administration. This symptom occurred only for a few days, and did not require weight 309Æ13) concentrations were measured by a any specific treatment. No significant laboratory high-performance liquid chromatographic (HPLC) abnormalities occurred in the subjects, and phys- method (18, 19). The limit of quantification of me- ical examinations revealed no abnormal findings at floquine and its carboxylic acid metabolite was 62Æ5 ng/mL. The intraday coefficient of variation ofboth mefloquine and its carboxylic acid metabolite was 1Æ60–9Æ07%, whereas the interday coefficient ofvariation was 3Æ51–10Æ21%. The relative recovery of The mean plasma concentration–time profiles of standard mefloquine and its carboxylic acid meta- mefloquine and of its carboxylic acid metabolite bolite in human plasma was 83–98% and 89–100% co-administered with ketoconazole are shown inFig. 1 and the pharmacokinetic parameters aresummarized in Table 1.
The mean AUC0)t, t1/2, and Cmax values of The pharmacokinetic parameters were analysed mefloquine co-administered with ketoconazole using a one-compartmental model and WinNonlin increased by 79% (159Æ66 ± 33Æ28 vs. 286Æ05 ± version 4.1 (Pharsight, Mountain View, CA, USA).
64Æ25 mg/L/h; P < 0Æ001), 39% (322Æ68 ± 99Æ95 vs.
The total area under the plasma concentration–time 448Æ41 ± 103Æ88 h; P < 0Æ05) and 64% (345Æ10 ± curve (AUC) was calculated by the linear trapezo- 43Æ22 vs. 567Æ65 ± 88Æ69 ng/mL; P < 0Æ001), respec- idal rule. The elimination rate constant (Ke) was tively when compared with mefloquine alone. The estimated from the least-squares regression slope mean AUC0)t, and Cmax of mefloquine carboxylic of the terminal plasma concentrations time course.
acid metabolite decreased by 28% (492Æ43 ± 141Æ66 The half-life (t1/2) of mefloquine and mefloquine vs. 352Æ29 ± 47Æ08 mg/L/h; P < 0Æ05) and 31% metabolite were calculated using the following (606Æ11 ± 184Æ00 vs. 419Æ65 ± 45Æ02 ng/mL; P < 0Æ05), respectively. The t1/2 value of the carboxylic acid metabolite decreased by 15% (679Æ08 ± 358Æ49 vs. 575Æ03 ± 82Æ28 h; P > 0Æ05) but was not signifi- The maximum plasma concentration (Cmax) and cantly different to the control values. The mean the time to reach Cmax (Tmax) were obtained from Tmax values for mefloquine and mefloquine the plasma concentration–time data.
carboxylic metabolite after co-administration ofmefloquine with ketoconazole were not signifi-cantly different from seen with mefloquine alone.
All results were expressed as mean ± standard deviation (SD). Differences in mefloquine andmefloquine metabolite pharmacokinetic parameter These results suggest that co-administered keto- among control and treatment groups were tested conazole increased the plasma concentration of by one-way ANOVA with P < 0Æ05 taken as the level mefloquine. The increase in AUC0)t (79%) and of significance. The effect of period, sequence and Cmax (64%) of mefloquine was likely the result of interaction were evaluated with the use of two-way decreased presystemic metabolism of mefloquine.
The rate of absorption of mefloquine was unlikely Ó 2005 Blackwell Publishing Ltd, Journal of Clinical Pharmacy and Therapeutics, 30, 285–290 to have been affected as there was no significantdifference in the Tmax of mefloquine with andwithout ketoconazole. The presystemic metabolism mefloquine alone mefloquine after ketoconazole of mefloquine probably involved intestinal andhepatic CYP3A4. The increase in elimination t1/2 of mefloquine in subjects with ketoconazole treatmentindicated an increased systemic metabolism of mefloquine. In addition, the AUC0)t and Cmax ofmefloquine carboxylic acid metabolite were signi-ficantly reduced with ketoconazole co-administra- tion. Reduced presystemic mefloquine metabolismis reflected in a decreased rate of metabolite for- mation. Ketoconazole appears to have reduced the Mefloquine metabolite after mefloquine alone metabolism of mefloquine during both presystemic Mefloquine metabolite after mefloquine + ketoconazole and elimination phases (increased Cmax and longert1/2 values for mefloquine when given with keto- conazole). The liver and intestine play an importantrole in the presystemic metabolism of many CYP3A4 substrates, and ketoconazole is a potentinhibitor of CYP3A4 in these organs. Therefore, the increased mean AUC0)t, Cmax and t1/2 of mefloqu- ine after single oral dose administration with ketoconazole for 10 days may be the result of inhibition of CYP3A4 by ketoconazole, which were similar to those occurring with quinine (12) as mefloquine (a) and its carboxylic acid metabolite (b) in mefloquine has a chemically structure related to eight healthy subjects after a single oral dose of 500 mg quinine. Significant quantities of CYP3A4 are mefloquine alone (d) or co-administration with 400 mg found in small bowel enterocytes and liver (20).
ketoconazole orally for 10 days (s). Data are mean ± SD.
CYP3A4 is the most abundantly expressed CYP Table 1. Pharmacokinetic parameters (mean ± SD) of mefloquine and its carboxylic acid metabolite in eight subjectsfollowing a single oral of dose 500 mg mefloquine alone or in combination with oral administration of 400 mg/dayketoconazole for 10 days Values are given as mean ± SD.
AUC, area under the plasma concentration–time curve; t1/2, elimination half-life; Tmax, time to reach Cmax; Cmax, maximum plasmaconcentration. Data are mean ± SD.
*P < 0Æ05, **P < 0Æ001 significantly different compared with control phase (one-way ANOVA).
Ó 2005 Blackwell Publishing Ltd, Journal of Clinical Pharmacy and Therapeutics, 30, 285–290 Plasma concentrations of antimalarial mefloquine and accounts for approximately 30–40% of the total metabolite is subject to several factors such as urine CYP contents in human adult liver and small pH, and changes in renal blood flow.
intestine (21). As ketoconazole is a potent inhibitor of CYP3A4 in both liver and small bowel entero- may be necessary to achieve chemosuppression cytes it provides the obvious explanation for the in P. faciparum infections. Plasma mefloquine strong interaction observed. We previously repor- concentrations from volunteers experiencing pro- ted that cimetidine, a potent CYP3A4 inhibitor, phylaxis failure were all less than 400 ng/mL, reduced the clearance, and prolonged the elimin- suggesting that higher mefloquine concentrations ation t1/2 of mefloquine in a similar manner to are necessary to suppress P. faciparum (18). In this quinine (22). Ketoconazole is also a potent P-gly- study, maximum plasma concentration of me- coprotein (P-gp) inhibitor, thereby decreasing floquine after mefloquine administration alone and co-administered with ketoconazole were metabolism (23). In animal studies co-administra- 345Æ10 ± 43Æ22 ng/mL and 567Æ65 ± 88Æ69 ng/mL tion of ketoconazole (50 mg/kg, i.v.) caused an respectively. Therefore, our results indicated that eightfold increase in brain level of nelfinavir and a ketoconazole (400 mg for 10 days) raised plasma 3Æ5-fold increase in plasma concentration in mice concentrations of mefloquine sufficiently for a (24). Both CYP3A4 and P-gp have broad substrate specificity. Therefore, there is striking overlap of This effect is beneficial in subjects who would substrate between CYP3A4 and P-gp. Because of overlapping substrate specificity, and because of co-expression of CYP3A enzymes and P-gp in theintestine, kidney and liver, it is conceivable that P-gp may play an important role in drug absorp-tion, by limiting drug transport from the intestinal Ketoconazole enhances plasma concentrations of lumen and metabolism (23). The fact that inhibition mefloquine considerably by inhibiting its meta- of P-gp by ketoconazole contributed to the bolism in the liver rather than the small intestine.
observed interaction with mefloquine, cannot be Inhibition of CYP3A4-mediated metabolism, is a excluded in this study. The higher t1/2 in subjects likely explanation. Both mefloquine and keto- with ketoconazole co-administration indicated a conazole are widely prescribed in some coun- decreased hepatic metabolism of mefloquine. This tries. Thus, clinicians should be aware of this suggests that ketoconazole inhibits the hepatic CYP3A4-mediated metabolism of mefloquine.
The significant decrease in the AUC0)t and Cmax of mefloquine carboxylic acid metabolite afterco-administration of ketoconazole is probably the This study was supported by grants from the Thai result of the cytochrome P450 by the latter. In Government, Faculty of Science, Graduate Studies, support, the t1/2 value of mefloquine carboxylic Prince of Songkla University, Thailand. We thank metabolite after ketoconazole co-administration F-Hoffmann-La Roche, Basel, Switzerland, for decreased by 15% compared wirh mefloquine donating standard mefloquine hydrochloride and alone. Differences in drug metabolism and their its carboxylic acid metabolite for use in HPLC determinants in human organisms have been intensively investigated over the years. In general,genetic factors (polymorphism) are more important than environmental ones. It was reported thatCYP3A4*1B carriers required more tacrolimus to 1. Palmer KJ, Holliday SM, Brogden RN (1993) reach target trough concentrations compared with Mefloquine: a review of its antimalarial activity, CYP3A4*1 homozygotes (25). However, among the pharmacokinetic properties and therapeutic efficacy.
Drugs, 45, 430–475.
latter, age, nutrition, disease and drug interaction 2. Simpson JA, Price R, ter Kuile F et al. (1999) Popu- were common factors altering drug metabolism. In lation pharmacokinetics of mefloquine in patients addition, renal elimination of either drug or Ó 2005 Blackwell Publishing Ltd, Journal of Clinical Pharmacy and Therapeutics, 30, 285–290 with acute falciparum malaria. Clinical Pharmacology 15. Suzuki S, Kurata N, Nishimua Y, Yasuhara H, Satoh T (2000) Effects of imidazole antimycotics on the 3. Karbwang J, White NJ (1990) Clinical pharmaco- liver microsomal cytochrome P450 isoforms in rats: kinetics of mefloquine. Clinical Pharmacokinetics, 19, comparison of in vitro and ex vivo studies. European Journal of Drug Metabolism and Pharmacokinetics, 25, 4. Nosten F, Price RN (1995) New antimalarials a risk- benefit analysis. Drug Safety, 12, 264–273.
16. Tsunoda SM, Velez RL, Von Moltke LL, Greenblatt 5. ter Kuile FO, Nosten F, Thieren M et al. (1992) High DJ (1999) Differentiation of intestinal and hepatic dose mefloquine in the treatment of multidrug cytochrome P4503A activity with use of midazolam resistant falciparum malaria. Journal of Infectious as an in vivo probe: effect of ketoconazole. Clinical Pharmacology and Therapeutics, 66, 461–471.
6. Mirghani RA, Hellgren U, Westerberg PA, Ericsson 17. Sikka SC, Swerdloff RS, Rajfer J (1985) In vitro inhi- O, Bertilsson L, Gustafsson LL (1999) The roles of bition of testosterone biosynthesis by ketoconazole.
cytochrome P450 3A4 and 1A2 in the 3-hydroxyla- tion of quinine in vivo. Clinical Pharmacology and 18. Crevoisier C, Handschin J, Barre J, Roumenov D, Kleinbloesem C (1997) Food increases the bioavaila- 7. Venkatakrishnan K, Von Moltke LL, Greenblatt DJ bility of mefloquine. European Journal of Clinical (2000) Effects of the antifungal agents on oxidative drug metabolism. Clinical Pharmacokinetics, 38, 111– 19. Ridtitid W, Wongnawa M, Mahatthanatrakul W, Chaipol P, Sunbhanich M (2000) Effect of rifampin 8. Bergqvist Y, Hellgren U, Churchill FC (1988) High- on plasma concentrations of mefloquine in healthy performance liquid chromatography assay for the volunteers. Journal of Pharmacy and Pharmacology, 52, simultaneous monitoring of mefloquine and its metabolite in biological samples using protein pre- 20. Villikka K, Kivisto KT, Backman JT, Olkkola KT, cipitation and ion-pair extraction. Journal of Chroma- Neuvonen PJ (1997) Triazolam is ineffective in patients taking rifampin. Clinical Pharmacology and 9. White NJ (1988) Drug treatment and prevention of malaria. European Journal of Clinical Pharmacology, 34, 21. Wildt SN, Kearns GL, Leeder JS, Anker JN (1999) Cytochrome P450 3A ontogeny and drug disposi- 10. White NJ (1996) Malaria. In: Cook GC, ed. Manson’s tion. Clinical Pharmacokinetics, 37, 485–505.
Tropical Disease. Philadelphia: WB Saunders, 1078– 22. Sunbhanich M, Ridtitid W, Wongnawa M, Aeksiri- pong S, Chamnongchob P (1997) Effect of cimetidine 11. Zhao XJ, Yokoyama H, Chiba K, Wanwimolruk S, on an oral single-dose mefloquine pharmacokinetics Ishizaki T (1996) Identification of human cytochrome in humans. Asia Pacific Journal of Pharmacology, 12, P450 isoforms involved in the 3-hydroxylation of quinine by human liver microsomes and nine 23. Lin JH (2003) Drug-drug interaction mediated by recombinant human cytochromes P450. Journal of inhibition and induction of P-glycoprotein. Advanced Pharmacology and Experimental Therapeutics, 279, 24. Choo EF, Leake B, Wandel C, Imamura H, Wood AJJ, 12. Mirghani RA, Hellgren U, Bertilsson L, Gustafsson Wilkinson GR, Kim RB (2000) Pharmacological LL, Ericsson O (2003) Metabolism and elimination of inhibition of P- glycoprotein transports enhances the quinine in healthy volunteers. European Journal of distribution of HIV-1 protease inhibitors into brain Clinical Pharmacology, 59, 423–427.
and testes. Drug Metabolism and Disposition, 28, 655– 13. Ridtitid W, Wongnawa M, Mahatthanatrakul W, Phaipenkong P, Sunbhanich M (2001) Effect of 25. Hesselink DA, van Schaik RHN, van der Heiden IP ketoconazole and itraconanazole on plasma concen- et al. (2003) Genetic polymorphisms of the CYP3A4, trations of quinine in normal healthy volunteers.
CYP3A5, and MDR-1 genes and pharmacokinetics of Thai Journal of Pharmacology, 23, 101–108.
the calcineurin inhibitors cyclosporine and tacro- 14. Venkatakrishnan K, Von Moltke LL, Greenblatt DJ limus. Clinical Pharmacology and Therapeutics, 74, (2000) Effects of the antifungal agents on oxidative Ó 2005 Blackwell Publishing Ltd, Journal of Clinical Pharmacy and Therapeutics, 30, 285–290
Federal Register / Vol. 78, No. 156 / Tuesday, August 13, 2013 / Notices Leslie Kux, 20405–0001, telephone 202–501–4755. Assistant Commissioner for Policy. SUPPLEMENTARY INFORMATION: [FR Doc. 2013–19523 Filed 8–12–13; 8:45 am] I. Background BILLING CODE 4160–01–P DEPARTMENT OF HEALTH AND HUMAN SERVICES Medical Foods; Second Edition.’’ This Case