The pharmacodynamic and pharmacokinetic interaction of flecainide acetate with propranolol: Effects on cardiac function and drug clearance

Summary The effect of aluminum phosphate on the bioavailability of ranitidine has been investigated in 10 young, healthy volunteers. Following a random cross over design, each subject took at a 1 week interval 150 mg ranitidine alone or with 11 g aluminum phosphate. Plasma and urine ranitidine levels were measured by HPLC. The antacid reduced both the maximum plasma ranitidine concentration by 40% and the area under the curve by 30%. Elimination of ranitidine was not changed. The results indicate that aluminum phosphate significantly diminished the bioavailability of ranitidine.     

Pharmacokinetics and pharmacodynamics of ramipril and piretanide administered alone and in combination

The pharmacokinetics and pharmacodynamics of single oral doses of 5 mg ramipril and 6 mg piretanide administered separately and in combination were determined in a single blind, randomised, 3-period cross-over study in 24 healthy male volunteers.The peak plasma concentrations of ramipril and ramiprilat increased slightly (from 11.9 to 14.8 ng/ml, and from 6.39 to 8.96 ng/ml, respectively) as did the area under the plasma concentration-time curve of ramipril (0–4 h) and ramiprilat (0–24 h) (from 15.8 to 19.8 ng·ml^–1·h, and from 63.4 to 74.6 ng·ml^–1·h, respectively). The urinary excretion of ramiprilat also rose (from 6.82 to 7.73 % of dose) following simultaneous treatment with piretanide. These effects were probably due to reduced first-pass metabolism of ramipril/ramiprilat to inactive metabolites. The blood pressure lowering effect, the time course of inhibition of ACE activity in plasma and the concentration-response relationship for the inhibition of plasma ACE activity were not affected by piretanide.The peak plasma concentration of piretanide was somewhat reduced (from 285 to 244 ng/ml) following simultaneous treatment with ramipril. No other pharmacokinetic parameter was affected. Piretanide increased urine flow, and sodium, chloride and potassium excretion, especially during the first 2 hours following administration. These pharmacodynamic parameters were not affected by ramipril.Thus, simultaneous administration of single oral doses of ramipril and piretanide caused modest changes in the peak and average plasma concentrations of both drugs, which did not lead to detectable alterations in the pharmacodynamic parameters measured in healthy volunteers.     

The pharmacokinetic and pharmacodynamic consequences of the co-administration of lamotrigine and a combined oral contraceptive in healthy female subjects

AIMS: To assess the pharmacokinetic and pharmacodynamic effects of co-administration of a combined oral contraceptive (ethinyloestradiol plus levonorgestrel) and lamotrigine. METHODS: Over a period of 130 days, healthy female subjects took lamotrigine (titrated up to 300 mg day(-1)) and the combined oral contraceptive, either individually or as co-therapy. Plasma ethinyloestradiol and levonorgestrel concentrations were measured in the presence and absence of lamotrigine, and serum lamotrigine concentrations were measured in the presence and absence of the combined oral contraceptive. Serum concentrations of follicle-stimulating hormone (FSH), luteinizing hormone (LH), progesterone, oestradiol and sex hormone binding globulin were also determined. RESULTS: Of the 22 enrolled subjects, 16 had evaluable pharmacokinetic data. The mean (90% CI) ratios of lamotrigine area under the concentration-time curve from 0 to 24 h (AUC(0,24 h)) and maximum observed concentration (C(max)) of lamotrigine when it was given with the combined oral contraceptive and during monotherapy were 0.48 (0.44, 0.53) and 0.61 (0.57, 0.66), respectively. Ethinyloestradiol pharmacokinetics were unchanged by lamotrigine, the mean combined oral contraceptive + lamotrigine : combined oral contraceptive alone ratios (90% CI) of the AUC(0,24 h) and C(max) of levonorgestrel were 0.81 (0.76, 0.86) and 0.88 (0.82, 0.93), respectively. FSH and LH concentrations were increased (by 4.7-fold and 3.4-fold, respectively) in the presence of lamotrigine, but the low serum progesterone concentrations suggested that suppression of ovulation was maintained. Intermenstrual bleeding was reported by 7/22 (32%) of subjects during co-administration of lamotrigine and combined oral contraceptive. CONCLUSIONS: A clinically relevant pharmacokinetic interaction was observed during co-administration of a combined oral contraceptive and lamotrigine. A dosage adjustment for lamotrigine may need to be considered when these agents are co-administered. A modest decrease in the plasma concentration of levonorgestrel was also observed but there was no corresponding hormonal evidence of ovulation.     

Lack of pharmacodynamic and pharmacokinetic interaction between pantoprazole and phenprocoumon in man

Objective: Pantoprazole is a selective proton pump inhibitor characterized by a low potential to interact with the cytochrome P450 enzymes in man. Due to the clinical importance of an interaction with anticoagulants, this study was carried out to investigate the possible influence of pantoprazole on the pharmacodynamics and pharmacokinetics of phenprocoumon. Methods: Sixteen healthy male subjects were given individually adjusted doses of phenprocoumon to reduce prothrombin time ratio (Quick method) to about 30–40% of normal within the first 5–9 days and to maintain this level. The individual maintenance doses remained unaltered from day 9 on and were administered until day 15. Additionally, on study days 11–15, pantoprazole 40 mg was given per once daily. As a pharmacodynamic parameter, the prothrombin time ratio was determined on days 9 and 10 (reference value) and on days 14 and 15 (test value), and the ratio test/reference was evaluated according to equivalence criteria. Results: The equivalence ratio (test/reference) for prothrombin time ratio was 1.02 (90% confidence interval 0.95–1.09), thus fulfilling predetermined bioequivalence criteria (0.70–1.43). The pharmacokinetic characteristics AUC_0–24h and C_max of S(−)-and R(+)-phenprocoumon were also investigated using equivalence criteria. Equivalence ratios and confidence limits of AUC_0–24h and of C_max of S(−)-phenprocoumon (0.93, 0.87–1.00 for AUC_0–24h; 0.95, 0.88–1.03 for C_max) and of R(+)-phenprocoumon (0.89, 0.82–0.96; 0.9, 0.83–0.98) were within the accepted range of 0.8–1.25. Conclusion: Pantoprazole does not interact with the anticoagulant phenprocoumon on a pharmacodynamic or pharmacokinetic level. Concomitant treatment was well tolerated. Received: 26 January 1996/Accepted in revised form:22 May 1996     

Lack of pharmacodynamic and pharmacokinetic interactions of the antihistamine ebastine with ethanol in healthy subjects

Summary We have given 12 healthy subjects the H₁-antihistamine ebastine (20 mg) or placebo in a double-blind, crossover study for one week each. The subjects were tested for drug effects on Day 6 of each period, and for interactions of ebastine with ethanol (0.8 g·kg^–1) on Day 7. On both days, the testing runs were done at baseline and at 2, 4, and 6 h after the drug. Performance was evaluated both objectively (digit symbol substitution, flicker fusion, Maddox wing, nystagmus, simulated driving, body balance) and subjectively (visual analogue scales) and with questionnaires. Venous blood samples were taken daily during maintenance and during each test run for assay of plasma carebastine. Blood ethanol concentrations were assayed with an Alcolmeter in the breath and directly in the blood. Plasma carebastine concentration reached a steady-state from Day 3 on; the mean concentrations in the morning were 92 µg·l^–1 on Day 6 and 104 µg·l^–1 on Day 7. The rise in plasma carebastine after an extra 20 mg of ebastine was accelerated but not increased by ethanol. Ebastine did not impair performance objectively or subjectively. It slightly improved body balance and reduced errors during simple tracking at 4 h. Blood ethanol concentrations peaked (mean 0.76 g·l^–1) at 1.5 h after ethanol intake. Ethanol impaired performance in most objective tests and produced clumsiness, muzziness, and mental slowness, but little drowsiness. Ebastine neither modified the blood ethanol concentrations nor increased the effects of ethanol. We conclude that treatment with 20 mg ebastine once daily for one week provides steady concentrations of carebastine in plasma without impairment of skilled performance or important interactions with alcohol.     

Semi-mechanistic pharmacokinetic/pharmacodynamic modelling of the antimalarial effect of artemisinin

PURPOSE: To characterize artemisinin pharmacokinetics (PK) and its antimalarial activity in vivo. METHODS: Artemisinin salivary concentration and parasite count data were obtained from Vietnamese malaria patients receiving two different dosage regimens. PK data were analysed using a previously developed semiphysiological model incorporating autoinduction of eliminating enzymes. A pharmacodynamic (PD) model reflecting different stages of the parasite life-cycle was developed and fitted to the data. The model included visible and invisible compartments as well as sensitive, insensitive, and injured parasite stages. Salivary artemisinin concentrations functioned as the driving force for the observed decrease in the number of parasites. RESULTS: Large interindividual variability was observed in both PK and PD data. The PK model described reasonably well the observed decrease in salivary concentrations after repeated drug administration. The preinduction hepatic extraction ratio of artemisinin was estimated to be 0.87 with a volume of distribution of 27 L. Artemisinin half-life averaged 0.7 h. Incorporation of a saturable hepatic elimination affecting the first-pass extraction as well as a higher intrinsic clearance in female patients resulted in the best fit of the model to the data. The PD model described the decrease in the number of parasites during the course of treatment well. The longest mean transit time of parasites from sensitive, visible to invisible to insensitive visible stages was found to be 34.5 h through one life-cycle. The half-life of injured parasites was 2.7 h. CONCLUSIONS: The proposed semimechanistic PK/PD model successfully described the time course of both salivary artemisinin concentrations after repeated dosing and the number of parasites in patients treated with the drug.     

Understanding how pharmacokinetic and pharmacodynamic differences of basal analog insulins influence clinical practice

This article reviews pharmacokinetic (PK) and pharmacodynamic (PD) concepts relating to the pharmacology of basal insulin analogs. Understanding the pharmacology of currently available long-acting basal insulins and the techniques used to assess PK and PD parameters (e.g. the euglycemic clamp method) is important when considering the efficacy and safety of these agents, and can help in understanding the rationale for specific dosing strategies when tailoring therapy for a specific patient. Basal insulins such as insulin glargine 100 units (U)/mL and insulin detemir show improved PK/PD characteristics compared with the intermediate-acting NPH insulin, with a longer duration of action, a more consistent glucose-lowering effect and less prominent concentration peaks. However, more recently developed basal insulins (insulin glargine 300?U/mL, and insulin degludec 100?U/mL and 200?U/mL) have PK/PD profiles closer to the physiologic profile of endogenous basal insulin owing to a more evenly distributed, predictable and prolonged time–action profile that exceeds 24?hours and improved within-patient variability in glucose-lowering effect. The clinical implications and relevance of these PK/PD profiles is explored, including the potential effect of PK/PD parameters on glycemic control and hypoglycemia, and the timing of dosing. The improved PK/PD properties of newer longer-acting basal insulins may translate into clinical benefits for patients with type 1 and type 2 diabetes, such as more consistent insulin levels in the blood over 24?hours, lower intra-patient variability, a reduced risk of nocturnal hypoglycemia, and more flexibility in dosing time, all of which are important to consider when choosing a basal insulin regimen.     

The pharmacokinetic and pharmacodynamic interaction between zileuton and terfenadine

Objectives: The effects of zileuton on terfenadine pharmacokinetics, and the effects of terfenadine alone and the combination on the duration of the QTc interval and the morphology of the TU complex were examined. Methods: The study was double-blind, randomized, placebo-controlled, two period cross-over in 16 healthy volunteers. During each period, subjects received 60 mg of terfenadine every 12 h on days 1 to 7 and 600 mg of either zileuton or placebo for zileuton every 6 h on days 1 to 10. Blood samples were obtained on days 7 to 10 and serial ECGs were performed on days –1 and 7 in both periods. Results: The combination of zileuton and terfenadine was well tolerated. Coadministration of zileuton with terfenadine resulted in a significant increase in the mean AUC and C_max of terfenadine by approximately 35% and the mean AUC and C_max of carboxyterfenadine by approximately 15%. The maximum concentration of terfenadine observed in the study was 9.6 ng · ml⁻¹. The addition of zileuton to terfenadine did not result in significant changes in the evaluated ECG-recordings (QTc interval and morphology of TU complex). The difference in means for both maximum and average QTc interval was very small (≤ 2.3 ms), and there were no clinically significant changes in individual values. Conclusions: The relatively small pharmacokinetic effect of zileuton on terfenadine metabolism, with no change in the QTc interval, is unlikely to be of clinical significance. The interaction is minimal in comparison to the background variability of the population. Received: 29 July 1996 / Accepted in revised form: 11 November 1996     

The use of pharmacokinetic and pharmacodynamic data in the assessment of drug safety in early drug development

The pharmaceutical industry continues to look for ways to reduce drug candidate attrition throughout the drug discovery and development process. A significant cause of attrition is due to safety issues arising either as a result of animal toxicity testing or in the clinical programme itself. A factor in the assessment of safety during early drug development is the pharmacokinetic profile of the compound. This allows safety data to be considered in the light of systemic drug exposure and therefore permits a quantitative assessment. This is particularly applicable when assessing the risk of a new chemical entity (NCE) in relation to safety parameters such as QT interval prolongation, where free plasma concentrations have been shown to be predictive of this property in relation to potency in preclinical testing. Prior to actual human exposure it is therefore important to be able to predict reliably the pharmacokinetic behaviour of an NCE in order to place such safety findings into a quantitative risk context. The emerging science of pharmacogenetics is likely to further our ability to assess the risk of NCEs to populations and individuals due to genetic variance. The drug metabolizing enzyme CYP2D6 has been recognized as providing the potential to result in widely differing systemic drug exposure in the patient population due to polymorphic expression. Further knowledge is likely to add to our understanding of population differences in exposure and response and aid in the identification of risk factors. One potential strategy for improving the effectiveness of the drug discovery process is to obtain clinical pharmacokinetic data more rapidly in order to assess more accurately the potential for both efficacy and safety of an NCE. Whilst procedures and technologies are available that allow this on the microdose scale, it is important that we recognize potential limitations of these approaches in order that they can be applied beneficially.     

Population pharmacokinetic and pharmacodynamic model of norvancomycin

去甲万古霉素群体药代动力学与药效学研究@张菁$Institute of Antibiotics, Huashan Hospital, Fudan University!Shanghai 200040, China @张婴元$Institute of Antibiotics, Huashan Hospital, Fudan University!Shanghai 200040, China @施耀国$Institute of Antibiotic     

家兔体内呋喃苯胺酸的药动学和药效学结合模型

用药动学-药效学结合模型对呋喃苯胺酸在家兔体内的处置和效应动力学作定量分析。呋喃苯胺酸的k_(eo),S,E_(max),EC_(50)分别为0.131±0.029min~(-1),2.21±0.61,6.5±0.6ml/min,3.49±0.77μg/ml。结果表明血浆与作用部位属于不同的房室,两者之间存在着一个平衡过程。     

Receptor-mediated pharmacokinetic/pharmacodynamic model of interferon-beta 1a in humans

Purpose. An integrated receptor-based pharmacokinetic/pharmaco- dynamic (PK/PD) model of interferon- 1a (IFN- 1a) previously developed for monkeys was used to capture the time-course of drug and induced neopterin concentrations after intravenous (IV) and subcutaneous (SC) dosing in humans. Methods. Data were extracted from the literature by digitalization. Single-dose (3 IV doses and 1 SC dose) PK/PD profiles were simultaneously fitted using the basic model and the ADAPT II computer program. Additional submodels incorporating neutralizing antibody formation and negative feedback inhibition were applied to account for drug accumulation and lower than expected neopterin concentrations encountered after multiple-dosing (1 SC dose every 48 hs). Results. The basic model jointly-captured the nonlinear PK behavior of the drug and induced neopterin concentrations after all single doses. Slow and incomplete absorption (F = 0.33) of the SC dose resulted in prolonged drug concentrations reflective of flip-flop kinetics. Despite lower drug concentrations, SC dosing produced a similar neopterin profile as compared with the IV doses; however, with a longer time to peak effect and slightly higher neopterin concentrations at later time points. The PD component of the model represents a modified precursor-dependent indirect response model driven by the amount of internalized drug-receptor complex. The latter stimulated a 6-fold increase in the production of the neopterin precursor (S_max = 5.89). Drug accumulation and lower than expected neopterin concentrations after multiple dosing were also captured after the inclusion of the submodels. Conclusions. The present integrated PK/PD model for IFN- 1a is mechanistic in nature with receptor-mediated disposition and dynamics and was successfully applied to human clinical data.     

Theoretical pharmacokinetic and pharmacodynamic simulations of drug delivery mediated by blood--brain barrier transporters

Pharmacokinetic/pharmacodynamic simulations were performed to assess the feasibility of central nervous system (CNS) drug delivery via endogenous transporters resident at the blood-brain barrier (BBB). Pharmacokinetic models were derived for intravenous bolus dosing of a hypothetical drug in the absence or presence of an endogenous, competing transport inhibitor. These models were linked to CNS pharmacodynamic models where the effect sites were either cell surface receptors or intracellularly localized enzymes. The response of the dependent parameter, the duration of effect (t(dur)), was examined in relationship to changes in the independent parameters, i.e. dose, elimination rate constant (k(e1)), BBB transport parameters (K(m1) and V(max1)) and EC(50) (effective concentration that elicits a 50% response). As expected, t(dur) increased with (a) increases in drug doses, (b) decreases in k(e1) or (c) decreases in EC(50), irrespective of the effect site. Surprisingly, endogenous transport inhibition produced decreases in drug terminal half-life and corresponding decreases in t(dur). Interestingly, t(dur) was independent of assigned transporter K(m) and V(max) when the dose/EC(50) ratio (dose/EC(50)) was >1 (irrespective of endogenous transport inhibition), but highly dependent on K(m1) and V(max1) when dose/EC(50) was (a) <1 (no endogenous transport inhibition) or (b) equal to 1 (with endogenous transport inhibition). Oral input of the endogenous transport inhibitor produced a decrease in t(dur) when the dose/EC(50) range was 0.1-10. These simulations highlight that (a) systemic pharmacokinetic and BBB transport parameters influence t(dur), (b) drug terminal half-life is inversely related to circulating levels of endogenous inhibitors, and (c) oral ingestion of endogenous transport inhibitor(s) reduces t(dur). Overall, these simulations provide insight for the feasibility of rational CNS drug design/delivery via endogenous transporters.     

Development of a model for integrated pharmacokinetic and pharmacodynamic studies of intravenous anaesthetic agents: Application to minaxolone

Summary This study reports an approach to the investigation of new intravenous anaesthetic agents. Minaxolone (0.5%) was administered to healthy young adult volunteers in three different phases of study: (i) Subanaesthetic constant-rate infusion of 0.01 mg·kg^–1min^–1 for 120 min; (ii) Subanaesthetic and anaesthetic infusion regimens of 0.05 mg·kg^–1 min^–1 for 60 min, followed immediately by 0.020 mg·kg^–1min^–1 for 60 min; approximately four weeks later the same subjects received infusions of 0.01 mg·kg^–1min^–1 and 0.015 mg·kg^–1min^–1 respectively for the same period of time; (iii) Bolus injections of 10 mg and 40 mg over 1 min, at 2 h apart. Similar pharmacokinetic parameters were derived from all three different regimens, most notably characterised by high total body clearance (1.6 to 3.2l·min^–1), correlating with rapid lucid clinical recovery of CNS function. Renal clearance was less than 0.5% of total body clearance, which was consistently 2 to 3 times the clearance of indocyanine green. Terminal half-life was short.The subanaesthetic infusion regimen of minaxolone produced a sleep-like state from which subjects were rousable, obeyed commands readily and maintained verbal contact with investigators, while remaining amnesic throughout. This occurred at blood minaxolone concentration of 0.14 to 0.15 mg·l^–1. In the second stage, general anaesthesia was induced at a mean blood minaxolone concentration of 0.24 mg·l^–1 (SD 0.11). Intravenous bolus injections of 40 mg minaxolone invariably induced anaesthesia with mean blood concentrations of 0.49 mg·l^–1 (SD 0.29) 2 min postinjection. Onset of anaesthesia was very rapid, mean 55 s (SD 10), with a consistent duration of anaesthesia (mean 23 min, SD 3). Recovery was very rapid and lucid, without any tendency to lapse back into sleep again.Generally, the incidence of adverse effects was greatest with anaesthetic bolus doses and least with subanaesthetic infusions. Whilst only mild excitatory movements were observed in 60% of subjects who received the subanaesthetic infusion, these increased in frequency and intensity with the anaesthetic infusions and occurred with the greatest severity in all subjects who received the 40 mg bolus injection. Tachycardia invariably was noted in all phases of study. A remarkably high incidence of respiratory upsets, in the form of tachypnoea, hyperventilation, apnoea, hiccoughs and laryngospasm, was observed with the 40 mg bolus dosage. Minaxolone, therefore, whilst possessing pharmacokinetic properties desirable of an IV anaesthetic agent, had disturbing clinical effects which may limit its clinical use. Using this approach, studies in only 15 volunteer subjects were successful in describing the pharmacokinetics, blood concentration-response relationships as well as the incidence and nature of side effects. On the basis of these data, it was possible to determine that the new drug, minaxolone, did not show sufficient promise to warrant further development. This methodology would seem to provide a useful model in the investigation of new intravenous anaesthetics to optimise patient safety and development costs.     

Pharmacokinetic and pharmacodynamic interactions of bretazenil and diazepam with alcohol

1 Interaction between alcohol and bretazenil (a benzodiazepine partial agonist in animals) was studied with diazepam as a comparator in a randomized, double-blind, placebo controlled six-way cross over experiment in 12 healthy volunteers, aged 19−26 years.
2 Bretazenil (0.5  mg), diazepam (10  mg) and matching placebos were given as single oral doses after intravenous infusion of alcohol to a steady target-blood concentration of 0.5  g l⁻¹ or a control infusion of 5% w/v glucose at 1 week intervals.
3 CNS effects were evaluated between 0 and 3.5  h after drug administration by smooth pursuit and saccadic eye movements, adaptive tracking, body sway, digit symbol substitution test and visual analogue scales.
4 Compared with placebo all treatments caused significant decrements in performance. Overall, the following sequence was found for the magnitude of treatment effects: bretazenil+alcohol>diazepam+alcohol≥bretazenil> diazepam>alcohol>placebo.
5 There were no consistent indications for synergistic, supra-additive pharmacodynamic interactions between alcohol and bretazenil or diazepam.
6 Bretazenil with or without alcohol, and diazepam+alcohol had marked effects. Because subjects were often too sedated to perform the adaptive tracking test and the eye movement tests adequately, ceiling effects may have affected the outcome of these tests.
7 No significant pharmacokinetic interactions were found.
8 Contrary to the results in animals, there were no indications for a dissociation of the sedative and anxiolytic effects of bretazenil in man.     

Pharmacokinetic and pharmacodynamic drug interactions between digoxin and macrogol 4000, a laxative polymer, in healthy volunteers

AIMS: The aim of this study was to examine the bioequivalence between a single oral dose of digoxin administered alone and with a coadministration of macrogol 4000 (a laxative polymer) in 18 healthy volunteers. METHODS: This was an open, randomised, two-way cross-over study, with a single dose oral administration of 0.5 mg digoxin administered alone or in combination with macrogol 4000, 20 g day-1 during 8 days. Pharmacokinetics of digoxin, heart rate and PR ECG interval at rest were assessed. RESULTS: Macrogol 4000 coadministration was associated with a 30% decrease of digoxin AUC and a 40% decrease in its Cmax (P<0.05). Digoxin tmax and t1/2,z were not significantly altered. Heart rate and PR interval did not differ during the two therapeutic sequences, digoxin alone and digoxin in combination. CONCLUSIONS: Macrogol 4000 coadministration interacts with single-dose digoxin pharmacokinetics. This is most likely due to a reduction of the intestinal absorption of digoxin. However, there was no consequence of this interaction on heart rate and AV conduction.     

Effect of piperine on bioavailability and pharmacokinetics of propranolol and theophylline in healthy volunteers

Summary The effect of piperine on the bioavailability and pharmacokinetics of propranolol and theophylline has been examined in a crossover study. Six subjects in each group received a single oral dose of propranolol 40 mg or theophylline (150 mg) alone or in combination with piperine 20 mg daily for 7 days. An earlier t_max and a higher C_max and AUC were observed in the subjects who received piperine and propranolol. It produced a higher C_max, longer elimination half-life and a higher AUC with theophylline.In clinical practice, the enhanced systemic availability of oral propranolol and theophylline could be exploited to achieve better therapeutic control and improved patient compliance.     

Population pharmacokinetic and pharmacodynamic modelling of the antimalarial chemotherapy chlorproguanil/dapsone

AIMS: To determine the population pharmacokinetics of chlorproguanil, dapsone and the active metabolite of chlorproguanil, chlorcycloguanil; and to estimate the duration of parasitocidal activity for chlorpoguanil/dapsone against Plasmodium falciparum isolates of varying sensitivity. METHODS: Rich and sparse pharmacokinetic data were collected prospectively from: healthy volunteers (n=48) and adults (n=65) and children (n=68) suffering from P. falciparum malaria. All subjects received 2.0 mg kg-1 of chlorproguanil and 2.5 mg kg-1 of dapsone. RESULTS: The population pharmacokinetic parameter estimates for chlorproguanil were ka=00.09 h-1 (intersubject variability was 44%), CL/F=51.53 l h-1 (57%), CLD/F=54.67 l h-1, V1/F=234.40 l (50%) and V2/F=1612.75 l; for dapsone were ka=00.93 h-1, CL/F=1.99 l h-1 (72%) and V/F=76.96 l (48%); and for chlorcycloguanil were CLm/Fm=3.72 l h-1 kg-1 (67%) and Vm/Fm=12.76 l kg-1 (64%). For dapsone, CL/F and V/F were both significantly positively correlated with body weight. For a 10-kg child, the mean duration of parasitocidal activity for chlorproguanil/dapsone against the three most susceptible P. falciparum strains was 4.5 days [5th and 95th percentiles 2.4, 7.3] for W282; 5.9 days (3.6, 9.7) for ItG2F6; and 6.1 days (3.7, 10.1) for K39. For an isolate with the ile-164-leu mutation, V1/S, activity ranged from 0.8 days (0.0, 3.3) for a 10-kg child to 1.8 days (0.0, 4.0) for a 60-kg adult. CONCLUSIONS: Plasmodium falciparum malaria has no effect on the pharmacokinetic parameters for chlorproguanil, dapsone or chlorcycloguanil. Chlorproguanil/dapsone will probably prove to be ineffective against parasite strains with the mutation ile-164-leu, were these to become prevalent in Africa.