| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
PHARMACOKINETICS |
From the Metabolism and Pharmacokinetic Department (Dr Ahmed, Dr Sharma, Mr Gautam, Mr Varshney, Dr Paliwal, Dr Batra) and Department of Medical Affairs and Clinical Research (Dr Kothari, Dr Ganguly, Dr Saha), Ranbaxy Research Laboratories, Haryana, India, and Medicines for Malaria Venture-MMV, International Center Cointrin, Geneva, Switzerland (Dr Moehrle).
Address for correspondence: Jyoti Paliwal, PhD, Metabolism and Pharmacokinetics Department, Ranbaxy Research Laboratories, Plot #20, Sector-18, Udhyog Vihar Industrial Area, Gurgaon-122015, Haryana, India; e-mail: jyoti.paliwal{at}ranbaxy.com.
 |
ABSTRACT |
|---|
 TOP ABSTRACT MATERIALS AND METHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
|---|
Key Words: Piperaquine • pharmacokinetics • safety • healthy • subjects
Piperaquine (PQ) is structurally related to chloroquine and acts through the chemical inhibition of parasite heme detoxification.1 The drug was shown to be effective against both Plasmodium vivax and Plasmodium falciparum, including strains of chloroquine-resistant P falciparum. Thus, PQ superseded chloroquine as the recommended antimalarial by the Chinese National Malaria Control Program in 1978.1,2 With the development of PQ-resistant strains of P falciparum and the emergence of artemisinin derivatives, its use declined during 1980s.1 However, in 1990, Chinese scientists rediscovered PQP as one of the drugs identified to be combined with short courses of artemisinin derivatives. It was thought that such a combination would provide an inexpensive, short-course treatment regimen with a high cure rate and good tolerability. This would also reduce transmission and provide protection against the development of parasite resistance. The same approach has also been endorsed by the World Health Organization (WHO).3,4 Since 1997, 3 such combination antimalarial products containing PQP have been marketed in China and several other Southeast Asian countries. These include CV8, Artecom (dihydroartemisinin [DHA], PQP, and trimethoprim), and Artekin (DHA and PQ).4 CV8 tablets consist of PQP (320 mg), DHA (32 mg), primaquine phosphate (5 mg), and trimethoprim (90 mg). Artekin tablets consist of PQP (320 mg) and DHA (40 mg). The total dose of PQP in CV8 and Artekin therapy is 2560 mg, administered over 3 days and 32 hours, respectively.4
Despite the widespread clinical use of PQP for more than 30 years, there is limited information available on the pharmacokinetics in humans. To the best of our knowledge, only 4 pharmacokinetic studies have been published.4-7 Although some preclinical animal toxicity data have been published,8,9 conventional phase I to IV evaluation has not been carried out. The efficacy studies reported in the Chinese medical literature were often not conducted and/or reported with the rigor of a modern-day clinical trial, and some aspects of drug development were not addressed at all.5 A recently published population pharmacokinetics study in malaria patients used a 2-compartment model to report terminal half-life of PQ as 23 days and 14 days in adults and children, respectively.5 To date, only 2 pharmacokinetic studies of PQ in healthy subjects have been published.6,7 With the widespread use of PQP in many artemisinin combination therapies, it is imperative that more data on the disposition of PQ in healthy humans are obtained. Such data will allow critical evaluation of the current dosing regimens, developed empirically from its use in the Chinese population.
The objective of the rising single-dose (RSD) and rising multiple-dose (RMD) studies reported in this article was to determine the safety, tolerability, and pharmacokinetics (PK) of PQ following oral doses in healthy human subjects.
|
MATERIALS AND METHODS |
|---|
|
TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
|---|
Exclusion criteria included participation of subjects in another investigational drug study or blood donation 3 months prior to the start of this study, in addition to receiving antimalarial treatment in the past 6 months or any other medications within 7 days of the start of the study. Subjects were also excluded if they had taken any other planned treatment during its course and until the study ends, including over-the-counter (OTC) products, vitamins, and/or mineral supplements. If subjects had a history of drug use, alcohol abuse (>2 drinks/day defined according to US Food and Drug Administration [FDA] dietary guidelines 2005), caffeine intake (>5 cups coffee/tea/day), or smoking (
5 cigarettes/day), they were also excluded from the study. Virology hepatitis B virus surface antigen (HBs Ag), hepatitis C virus antibodies (HCV Ab), human immunodeficiency virus 1/2 (HIV), and urine drug screening were performed at the time of screening.
All subjects provided written informed consent to participate in the trial, according to the ethical principles stated in the Declaration of Helsinki, the applicable guidelines for the International Conference of Harmonization-Good Clinical Practice (ICH-GCP), and the applicable laws and regulations of Switzerland. The study protocol was approved by the local (Canton Ticino) Research Ethics Committee (EC) authorities and by the Federal Health Authorities (Swissmedic) before the start of the study.
Study Design
Both the parts (RSD and RMD) of the study followed a similar protocol with a double-blind, randomized, placebo-controlled, parallel-group design. In the RSD study, 5 escalating single oral doses (500, 750, 1000, 1250, and 1500 mg) of PQP were administered to 40 healthy male subjects. One cohort, comprising 8 subjects, was allocated to each of the 5 dose levels. In each cohort, randomization was done such that 6 subjects received the active product (PQP) and 2 subjects received the matching placebo after overnight fasting.
In the RMD study, 4 escalating oral doses (500, 750, 1000, and 1500 mg) of PQP were administered once daily for 3 consecutive days to 32 healthy subjects. One cohort, comprising 8 subjects, was allocated to each of the 4 dose levels. In each cohort, randomization was done such that 6 subjects received the active product (PQP) and 2 subjects received the placebo after overnight fasting.
No subject was part of more than 1 treatment group. In both trials, dosing began with the lowest dose and was escalated following review of safety data from the preceding dose group. PQP or matching placebo dosages consisted of 500-mg or 750-mg tablets or a combination of both and were manufactured at a Good Manufacturing Practices (GMP)-compliant facility of Ranbaxy Laboratories Limited, India. The assay values for the active drug content were 101.52% and 101.7% for the 500-mg and 750-mg tablets, respectively. Doses were given with 180 mL of water.
In RSD study, 265 mL of blood was collected from each subject over a 60-day period. Around 880 venous blood samples (10 mL each) were collected from the forearm vein using an indwelling catheter with a switch valve into sodium citrate containing tubes at predose and 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 16, 24, 36, 48, and 72 hours postdose. Further blood samples were collected in the morning of days 5, 7, 14, 21, 30, 45, and 60. The first 2 mL of blood was discarded at each collection time.
In RMD study, 375 mL of blood was collected from each subject over a 60-day period. Around 1056 venous blood samples (10 mL each) were collected from the forearm vein using an indwelling catheter with a switch valve at predose and 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 16, and 24 hours postdose following day 1 and day 3 dosing. Further blood samples were collected following day 3 dosing at 36, 48, and 72 hours and in the morning of days 7, 14, 21, 30, 45, and 60. The first 2 mL of blood was discarded at each collection time.
Blood samples were placed on ice immediately after collection and centrifuged (1800 g) at 4°C for 10 minutes to separate the plasma within 15 minutes of collection. Each plasma sample was immediately divided into 2 aliquots and transferred to prelabeled polypropylene tubes and stored frozen at 
-20°C until analysis.
Safety Monitoring
The safety and the general tolerability of the drug were judged based on adverse events (AEs), vital signs, physical examinations, and laboratory tests. All observed or volunteered AEs were recorded after administration of each dose with regard to their time of onset, severity, duration, and possible relationship to the study drug. Vital signs (blood pressure, heart rate, and oral body temperature) of the subjects were recorded at the screening visit; predose; 1, 4, 12, 24, and 48 hours postdose; and the final visit. Full physical examination was performed during screening and at the end of the study. During the RSD study, the ECGs were performed at the screening visit; at baseline (predose); and 12 hours (before dinner), 48 hours, 14 days, 30 days, and 60 days postdose (final visit). During the RMD study, the measurements were performed at the screening visit, at baseline (predose), 12 hours (before dinner) and 48 hours after each administration, 14 days, and 30 days and 60 days after the first administration (final visit). Routine hematology, blood chemistry, and urinalysis laboratory tests were performed at screening and were repeated also on day 3 (48 hours postdose) of both study parts and at the end of the study (day 60).
Analytical Methods
Plasma concentrations of PQ were determined by a validated liquid chromatography/tandem mass spectrometry (LC/MS/MS) method. The method used a PerkinElmer 200 Series high-performance liquid chromatography system (PerkinElmer Instruments LLC, Shelton, Connecticut), equipped with a quaternary pump, degasser, autosampler, and thermostatted column compartment. The compounds were analyzed on a Chromolith SpeedROD RP-18e (Merck KGaA, Germany) chromatographic column (4.6 x 50 mm) maintained at ambient temperature (24 ± 2°C). The mobile phase, consisting of methanol, 10 mM ammonium acetate, ammonia, and formic acid (750:250:1.5:2.0), was pumped at a flow rate of 0.8 mL/min. Bisquinoline was used as the internal standard (IS). The retention times of PQ and bisquinoline were 0.95 to 1.30 and 1.10 to 1.40 minutes, respectively.
Mass detection was performed on an API 4000 Q-Trap triple quadrupole instrument (Applied Biosystems MDS SCIEX, Toronto, Canada) using a turbo electrospray interface in positive ionization mode. Multiple-reaction monitoring was carried out with a dwell time of 200 ms per transition. The precursor to product ion transitions of m/z 535.3
288.2 and m/z 409.1205.2 were used to measure PQ and IS, respectively. The settings were optimized, and the instrument was operated with an ion spray voltage of 5.5 kV, back pressures for collision gas of 6 psi, curtain gas of 20 psi, nebulizer gas of 25 psi, and heater gas of 60 psi. Nitrogen was used as curtain and collision gas. The heater and nebulizer gas was zero air. The source temperature was 400°C. The collision energy was optimized to 45.1 and 47 eV for PQ and IS, respectively.
All plasma samples were shipped on dry ice and stored in a freezer maintained below -50°C. PQ and IS were extracted from 50 µL samples using protein precipitation with 300 µL acetonitrile. The samples were vortexed and centrifuged at 10 000 rpm for 10 minutes, and 10 µL of the clear supernatant was injected into the LC/MS/MS for analysis.
The lower limit of quantitation for PQ in plasma was 1.0 ng/mL, with a linear calibration range up to 250.2 ng/mL. Samples having a concentration greater than 250.2 ng/mL were diluted with blank plasma for analysis. Quality control (QC) samples at 3 levels—low (3 ng/mL), middle (100 ng/mL), and high (200 ng/mL)—were used during routine analysis. The precision and accuracy of QC samples during analysis of samples ranged from 5.67% to 19.05% and 94.06% to 108.46%, respectively. The precision and accuracy for calibration curve standards and QC samples met the acceptance criteria as per US FDA guidelines.10
Pharmacokinetic Evaluation
The plasma concentration-time data of PQ for each subject were analyzed with the noncompartmental method using validated WinNonlin Professional software (Version 4.1, Pharsight, Cary, North Carolina). Pharmacokinetic parameters for PQ included maximum observed concentration (Cmax), time to achieve Cmax (tmax), terminal elimination half-life (t
), area under the curve from time 0 to infinity (AUC0-
), area under the curve from time 0 to last observed concentration time t (AUC0-t) or within a 24-hour dosing interval (AUC0-24), oral plasma clearance (CL/F), and oral apparent volume of distribution (Vd/F). Cmax and tmax values were obtained directly from the data. The terminal elimination half-life was estimated as 0.693/
, where is the absolute value of the slope of the log-linear phase. AUCs were calculated by the trapezoidal rule. AUC0- was calculated as AUC0-t + Clast/, where Clast is the last quantifiable concentration. In the RMD study, only tmax, Cmax, and AUC0-24 were reported on day 1. All other pharmacokinetic parameters similar to those in the RSD study were evaluated on day 3, following last dose. The accumulation ratio (Ro) was calculated as the ratio of AUC0-24 on day 3 to the day 1 values.
Statistical Analysis
Single- and multiple-dose pharmacokinetic parameters are expressed as arithmetic mean, geometric mean, and standard deviation (SD) unless noted. A nonlinear power model was used to assess dose proportionality11 using SAS Version 8.2 (SAS Institute, Inc, Cary, North Carolina). The proportional relationship between each parameter and dose is written as a power function: parameter = a·doseb, where a is a constant, b is the proportionality constant, and parameter is AUC0-, AUC0-t, or Cmax. Log transformation of the equation changes into a linear form as log parameter = log a + b·log dose. The relationship is dose proportional if b = 1 and 95% confidence intervals (CIs) include unity. The exponent of the power function, with 95% CI, was fitted to the individual Cmax and AUC data. One-way analysis of variance (ANOVA) for testing dose dependency was performed using GraphPad Prism Version 4.00 for Windows (GraphPad Software, San Diego, California).
|
RESULTS |
|---|
|
TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
|---|
Ten AEs were recorded during the single-dose part of the study. Nine subjects were affected by these events, which were of mild to moderate intensity. Adverse events occurred after administration of each tested dose level of PQP, whereas no AE occurred to subjects receiving a single dose of PQP matching placebo. Five AEs were judged not to be related to the study treatment, whereas the other 5 were judged to be unlikely related. The most frequent AE was headache; other AEs included upper respiratory tract infection viral NOS (not otherwise specified) and flu-like illness.
Fourteen AEs, mild to moderate in intensity, were recorded during the multiple-dose part of the study and occurred in 10 subjects. Ten events were judged not to relate to the study treatment, whereas the other 4 AEs were judged as probably related to the treatment. Two probably related AEs were 2 different episodes of epigastric discomfort and 1 episode of vomiting. These 3 AEs occurred to the same subject, who received the treatment with piperaquine 500 mg OD for 3 consecutive days. The fourth probably related AE was an episode of headache, which occurred to 1 subject receiving the treatment with placebo for 3 consecutive days. Among all 14 AEs, the most frequent was upper respiratory tract infection viral NOS, though devoid of relationship to the treatment.
No significant effect of piperaquine on vital signs, ECGs, or laboratory parameters was observed. The frequency of observed ECG abnormalities was not affected by the treatment significantly. A statistical analysis performed on laboratory abnormalities and proportion of subjects affected by at least 1 abnormality did not detect any significant difference after treatment with piperaquine. Changes in ECG parameters at postdose versus screening and predose values were analyzed. The differences did not show any correlation with the study medication or dose and were not of clinical significance.
Single-Dose Pharmacokinetics
Mean plasma concentrations versus time profiles for PQ following the administration of single oral doses of PQP are presented in Figure 1. Single-dose pharmacokinetic parameters for PQ are presented in Table I.
|
|
The median time (tmax) to reach Cmax of PQ was between 2.5 and 4.5 hours postdose; thereafter, plasma piperaquine concentrations declined with a mean apparent terminal half life of approximately 11 to 18 days across the doses. One subject in the 750-mg dose group had considerably lower concentrations at all time points as compared with other subjects and had concentrations only until 96 hours. The half-life determined in this subject was 1.2 days. No reason could be assigned to this unusual finding. Average Cmax increased from 41.6 to 147 ng/mL, and AUC0- increased from 2969 to 7043 ng·h/mL at single-dose levels from 500 to 1500 mg (Table I). The plasma concentration-time profiles of PQ exhibited irregular absorption with multiple peaks at each dose level. The PQP dose level increased in the ratio of 1.0:1.5:1.3:1.3:1.2, whereas mean PQ Cmax, AUC0-t, and AUC0- increased in the ratio of 1.0:1.4:0.8:1.5:2.2, 1.0:1.1:1.3:1.0:1.8, and 1.0:1.2:1.1:1.1:1.6, respectively. The extent of deviation from dose proportionality, as given by the exponent of the power function, was fitted to the individual Cmax, AUC0-t, and AUC0- data. The exponents of the power model were 0.82, 0.73, and 0.69 for Cmax, AUC0-t, and AUC0-, respectively, indicating a less than dose-proportional relationship (relationship would be proportional if exponent was 1). The 95% CIs (0.11 to 1.53, 0.02 to 1.44, -0.03 to 1.42) around the mean exponents included unity, suggesting dose proportionality. Based on these results and visual inspection of linear regression graphs (Figures 2 and 3), the dose-exposure relationship can be concluded to be less than dose proportional and linear. The oral plasma clearance was independent (P > .05) of the doses administered. The oral apparent volume of distribution was also independent (P > .05) of the doses administered (except 500 vs 1250 mg; P < .05).
|
|
Multiple-Dose Pharmacokinetics
Mean plasma concentration versus time profiles for PQ following first-dose administration of PQP on day 1 and last-dose administration on day 3 are presented in Figure 4 and Figure 5, respectively. Plasma pharmacokinetic parameters for PQ are presented in Table II.
|
|
|
The plasma concentration profiles and exposures (Cmax and AUC0-24) of PQ following first dose on day 1 of the RMD evaluation were similar to those observed in the RSD trial. An accumulation ratio of approximately 3 to 7 was observed based on day 3 to day 1 ratios of AUC0-24 (Table II).
Following day 1 dosing, sampling was done until 24 hours, and because mean AUC0-24 represented less than 10% of AUC0- on day 3, only the relationship between Cmax and dose is reported. There was an approximately dose-proportional increase in Cmax values of PQ (Figure 6). The PQP dose level increased in the ratio of 1.0:1.5:1.3:1.5, whereas mean PQ Cmax increased in the ratio of 1.0:1.3: 1.4:2.2. The exponent of the power model for Cmax was 1.19, indicating a linearly dose-proportional relationship. The 95% CIs (0.23-2.15) around the mean exponents included unity, suggesting dose proportionality.
|
increased in the ratio of 1.0:2.2:1.2:1.3, 1.0:1.7:1.1:1.0, and 1.0:1.7:1.0:1.1, respectively. The exponents of the power model were 1.07, 0.59, and 0.58 for Cmax, AUC0-t, and AUC0-, respectively, indicating a less than dose-proportional relationship for AUC and proportional relationship for Cmax. The 95% CIs (0.46-1.68, 0.10-1.08, 0.07-1.10) around the mean exponents included unity, suggesting dose proportionality. Based on statistical analysis and visual inspection of linear regression graphs (Figures 7 and 8), the dose-exposure relationship can be concluded to be less than dose proportional and linear. The oral plasma clearance and apparent volume of distribution were independent (P > .05) of the doses administered.
|
|
|
DISCUSSION |
|---|
|
TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
|---|
In this study, the pharmacokinetics of PQ were less than dose proportional and linear. The mean apparent terminal half-life of PQ following single- and multiple-dose administration ranged from 11 to 23 days. This is consistent with that reported by Hung et al5 in malaria patients using the population approach. Roshammar et al7 fitted PQ concentration-time data in healthy subjects to a 2-compartment disposition model and reported a mean half-life of 11.7 (8.3-15.7) days with the population pharmacokinetic approach. In these studies,5,7 blood sampling was done for 35 and 29 days postdose, respectively. In the study conducted by Hung et al,5 3 of the 38 adult patients had detectable plasma PQ concentrations at the last sampling point (35 days), suggesting a long terminal half-life of 23 (19-28) days. The terminal elimination phase of PQ is critical for the posttreatment prophylactic effect and propensity to develop resistance.13 Tarning et al13 have reported a 33-day (lower limit of quantification [LLOQ], 2.5 ng/mL) apparent half-life of PQ following oral administration of 3 Artekin tablets under fed conditions and sampling for 93 days. They inferred that previously published terminal half-life values of the PQ are likely to be underestimates resulting from insufficient assay sensitivity and a shorter duration of sampling with oversimplified fitting of a 2-compartment model.13 In present study, blood samples were collected until 60 days from the time of first dosing and were analyzed using a highly sensitive assay with LLOQ as 1 ng/mL. This increased sensitivity allows quantification of PQ in plasma for much longer than in previous studies.14 The maximum terminal half-life observed in our study was 38 days, which is consistent with that reported in the literature.13 The determination of the half-life of long-acting drugs also depends on the number of points used in calculating terminal phase. Tarning et al13 estimated terminal plasma half-lives (based on all measurements from day 10 onwards) of 14, 30, and 33 days following blood sampling until 21, 64, and 93 days, respectively. The estimated terminal half-life was as long as 80 days, when based only on the last 3 measured concentrations. In the present study, the terminal half-lives were estimated by pharmacokinetic software (WinNonlin Professional, Version 4.1), based on default criteria of selecting the terminal phase, in the noncompartmental (NCA) module, for noncompartmental analysis.
A recent crossover study conducted in healthy Caucasian subjects compared the bioavailability of PQP tablets under fasting and after a standard high-fat breakfast.6 After the high-fat meal, both maximum serum concentrations and area under the concentration-time curve increased significantly, suggesting that the absorption of PQ may be facilitated by the presence of fat in the diet. The exposures in fasted subjects receiving the 500-mg dose in the present study were similar to that reported earlier.6
Following once-daily dosing of PQP for 3 consecutive days, the accumulation ratio of PQ ranged from 3 to 7. The observed accumulation of PQ is consistent with its long elimination half-life. Piperaquine displays multiphasic kinetics with a very slow 
-phase, and accumulation of PQ is governed not only by the terminal elimination phase but also by the disposition of PQ. Piperaquine has been reported to accumulate preferentially in the liver, kidney, and spleen of mice.12
Over the dose ranges studied, the systemic exposures (AUC) of PQ following single (RSD) and multiple (RMD, day 3) doses were less than dose proportional and linear. Variability in pharmacokinetic parameters of PQ following single and multiple dosing was quite high. Between-subject variability for AUC0- following single dosing ranged from 29% to 69% but ranged from 25% to 57% after multiple dosing (day 3). This variability is consistent with that reported in the literature.6
Piperaquine phosphate was well tolerated by all the subjects following single and multiple oral doses. Even with the high exposures attained in this multiple-dose study, no clinically significant changes in physical examination, vital signs, or laboratory measurements were observed during the course of the study.
In conclusion, PQP was well tolerated following single and multiple doses. The extent of systemic exposure to PQ increased in a less than dose-proportional and linear manner, with high interindividual variability, after single and once-daily (500-1500 mg) oral administration. Piperaquine exhibits 3- to 7-fold accumulation following once-daily dosing for 3 days. Multiple peaks were observed in the plasma PQ concentration-time profiles. Plasma concentrations of PQ were measurable up to 60 days following single and multiple dosing, with the LLOQ as 1 ng/mL. The mean terminal half-lives ranged from 11 to 18 days following single-dose administration and from 17 to 23 days following multiple-dose administration.
|
ACKNOWLEDGEMENTS |
|---|
|
TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
|---|
|
REFERENCES |
|---|
|
TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
|---|
1. Davis TME, Hung TY, Sim IK, Karunajeewa HA, Ilett KF. Piperaquine: a resurgent antimalarial drug. Drugs. 2005;65: 75-87.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
2. Hien TT, Dolecek C, Mai PP, et al. Dihydroartemisinin-piperaquine against multidrug-resistant Plasmodium falciparum malaria in Vietnam: randomized clinical trial. Lancet. 2004;363: 18-22.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
3. World Health Organization. Antimalarial Drug Combination Therapy. Geneva, Switzerland: WHO Technical Consultation; 2001.
4. Hung TY, Davis TME, Ilett KF. Measurement of piperaquine in plasma by liquid chromatography with ultraviolet absorbance detection. J Chromatogr B. 2003;791: 93-101.[CrossRef]
5. Hung TY, Davis TME, Ilett KF, et al. Population pharmacokinetics of piperaquine in adults and children with uncomplicated falciparum or vivax malaria. Br J Clin Pharmacol. 2004;57: 253-262.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
6. Sim IK, Davis TME, Ilett KF. Effects of a high-fat meal on the relative oral bioavailability of piperaquine. Antimicrob Agents Chemother. 2005;49: 2407-2411.
7. Roshammar D, Hai TN, Hietala SF, Huong NV, Ashton M. Pharmacokinetics of piperaquine after repeated oral administration of the antimalarial combination CV8 in 12 healthy male subjects. Eur J Clin Pharmacol. 2005;62: 335-341.[CrossRef][Web of Science]
8. Sheng N, Jiang W, Tang HL. Pre-clinical toxical study of new antimalarial agents: II. Piperaquine phosphate and its compound `Preventive no. 3.' Acad J Second Mil Med Coll. 1981;1: 40-46.
9. Zhao HJ, Xia YY, Zheng Z. Pre-clinical toxicity study of new antimalarial agents: IV. Liver ultrastructure changes affected by antimalarial agent, compound tablet of piperaquine phosphate and sulfadoxine. Acad J Second Mil Med Coll. 1981;1: 47-48.
10. US Food and Drug Administration. Guidance for Industry: Bioanalytical Method Validation. Rockville, MD: US Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research; 2001.
11. Gough K, Hutchison M, Keene O, et al. Assessment of dose proportionality: report from the statisticians in the pharmaceutical industry/pharmacokinetics UK joint working party. Drug Inform J. 1995;29: 1039-1048.
12. Chen Q, Deng J, Wu D. Study on absorption, distribution and excretion of 14C-piperaquine phosphate and 14C-piperaquine in mice. Pharm Ind. 1979;8: 19-23.[Medline] [Order article via Infotrieve]
13. Tarning J, Lindegardh N, Anneberg A, et al. Pitfalls in estimating piperaquine elimination. Antimicrob Agents Chemother. 2005;49: 5127-5128.
14. Lindegardh N, White NJ, Day NPJ. High throughput assay for the determination of piperaquine in plasma. J Pharm Biomed Anal. 2005;39: 601-605.[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
CiteULike 
Connotea 
Del.icio.us 
Digg 
Reddit 
Technorati What's this?
This article has been cited by other articles:
|
|
 |
|
  N. T. Chinh, N. N. Quang, N. X. Thanh, B. Dai, J. P. Geue, R. S. Addison, T. Travers, and M. D. Edstein Pharmacokinetics and Bioequivalence Evaluation of Two Fixed-Dose Tablet Formulations of Dihydroartemisinin and Piperaquine in Vietnamese Subjects Antimicrob. Agents Chemother., February 1, 2009; 53(2): 828 - 831. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. T. Chinh, N. N. Quang, N. X. Thanh, B. Dai, T. Travers, and M. D. Edstein Pharmacokinetics of the Antimalarial Drug Piperaquine in Healthy Vietnamese Subjects Am J Trop Med Hyg, October 1, 2008; 79(4): 620 - 623. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
