Population pharmacokinetics of the new antimalarial agent tafenoquine in Thai soldiers

AIMS: To describe the population pharmacokinetics of tafenoquine in healthy volunteers after receiving tafenoquine for malaria prophylaxis. METHODS: The population consisted of 135 male Thai soldiers (mean age 28.9 years; weight 60.3 kg). All soldiers were presumptively treated with artesunate for 3 days plus doxycycline for 7 days to remove any pre-existing malaria infections. After the treatment regime, 104 soldiers (drug group) received a loading dose of 400 mg tafenoquine base daily for 3 days followed by 400 mg tafenoquine monthly for 5 consecutive months. In the placebo group, 31 soldiers were infected with malaria during the study period. They were re-treated with artesunate for 3 days plus doxycycline for 7 days followed by a loading dose of 400 mg tafenoquine daily for 3 days and then 400 mg tafenoquine weekly for prophylaxis. Blood samples were randomly collected from each soldier on monthly and weekly prophylaxis. Plasma tafenoquine concentrations were measured by h.p.l.c. Population pharmacokinetic modelling was performed using NONMEM. RESULTS: A one-compartment model was found best to describe the pharmacokinetics of tafenoquine after oral administration. Age and weight influenced volume of distribution (V/F), and subjects who contracted malaria had higher clearance (CL/F), but none of these factors was considered to have sufficient impact to warrant change in dosing. The population estimates of the first-order absorption rate constant (Ka), CL/F and V/F were 0.694 h(-1), 3.20 l h(-1) and 1820 l, respectively. The intersubject variability in these parameters (coefficient of variation, CV%) was 61.2%, 25.3% and 14.8%, respectively. The absorption and elimination half-lives were 1.0 h and 16.4 days, respectively. The residual (unexplained) variability was 17.9%. CONCLUSIONS: The population pharmacokinetics of orally administered tafenoquine have been determined in Thai soldiers under field conditions. This information, together with its known potent antimalarial activity, portends well for the application of tafenoquine as a useful prophylactic drug or for short-term radical treatment of vivax malaria.     

The single dose kinetics of chloroquine and its major metabolite desethylchloroquine in healthy subjects

Summary The kinetics and disposition of chloroquine (CQ) and its metabolite monodesethylchloroquine (CQM) were investigated in 5 healthy volunteers after incremental (150–300–600 mg CQ base) single oral doses of CQ. The analytical method used (HPLC and fluorescence detection) is the most sensitive known method for CQ and CQM. Plasma and whole blood concentrations of CQ, CQM and a third metabolite, bidesethylchloroquine (CQMM), were determined. The kinetics of CQ was found to be unique. The best fit was obtained by a multicompartmental model. The biological half-life appeared to be between 30–60 days; the volume of distribution (V_d) was 800l/kg, and the clearance 11/h/kg when calculated from plasma data. The whole blood concentrations were 8–10 times higher than in plasma, and consequently the V_d and whole blood clearance were 10 times lower. The kinetics changed as the dose was increased. An indication of capacity-limited steps in CQ disposition was found, as the rate constants decreased even though the clearance remained the same. The intrinsic half-life of CQM was 1/4 of that of CQ, but was prolonged after the highest dose of CQ. The present knowledge of CQ kinetics could provide a basis for revision of current dosage regimens in malaria suppression and rheumatoid disease to ensure efficacious and safe therapy.     

Pharmacokinetic interactions of efavirenz and voriconazole in healthy volunteers

AIMS

Co-administration of standard-dose voriconazole and efavirenz results in a substantial decrease in voriconazole levels, while concurrently increasing efavirenz levels. Hence, concomitant use of standard doses of these drugs was initially contraindicated. This study assessed different dose combinations of efavirenz and voriconazole, with the goal of attaining a dose combination that provides systemic exposures similar to standard-dose monotherapy with each drug.

METHODS

This was an open-label, four-treatment, multiple-dose, fixed-sequence study in 16 healthy males. Steady-state pharmacokinetics were assessed following two test treatments (voriconazole 300 mg q12 h + efavirenz 300 mg q24 h and voriconazole 400 mg q12 h + efavirenz 300 mg q24 h) and compared with standard-dose monotherapy (voriconazole 200 mg q12 h or efavirenz 600 mg q24 h).

RESULTS

Dose adjustment to voriconazole 300 mg q12 h with efavirenz 300 mg q24 h decreased voriconazole area under the concentration–time curve (AUC_τ) and maximum concentration (C_max), with changes of −55% [90% confidence interval (CI) −62, −45] and −36% (90% CI −49, −21), respectively, when compared with monotherapy. Voriconazole 400 mg q12 h plus efavirenz 300 mg q24 h decreased voriconazole AUC_τ (−7%; 90% CI −23, 13) and increased C_max (23%; 90% CI −1, 53), while increasing efavirenz AUC_τ (17%; 90% CI 6, 29) and not changing C_max when compared with the respective monotherapy regimens. No serious adverse events were observed with voriconazole plus efavirenz.

CONCLUSIONS

When co-administered, voriconazole dose should be increased to 400 mg q12 h and efavirenz dose decreased to 300 mg q24 h in order to provide systemic exposures similar to standard-dose monotherapy.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT

• Efavirenz 400 mg q24 h reduces exposure to voriconazole 200 mg q12 h when the two drugs are co-administered.
• Furthermore, voriconazole increases the systemic exposure of efavirenz.
• Co-administration was therefore initially contraindicated.

WHAT THIS STUDY ADDS

• The doses of efavirenz and voriconazole can be adjusted to provide adequate exposure to both drugs when the two are co-administered, without compromising safety.
• Appropriate adjustment of doses for both drugs may thus represent an alternative to a mere contraindication.

     

Population pharmacokinetics of chloroquine and sulfadoxine and treatment response in children with malaria: suggestions for an improved dose regimen

AIMS

To describe the pharmacokinetics of chloroquine (CQ) and sulfadoxine (SDx), and to identify predictors of treatment response in children with malaria given the CQ + SDx and pyrimethamine (PYR) combination.

METHODS

Eighty-six Ugandan children with uncomplicated falciparum malaria, 6 months to 5 years old, were randomly treated with prepacked fixed-dose CQ + SDx/PYR. The youngest children (<24 months) received half strength and the older (>24 months) full strength treatment. The reported day 14 failure rates were 48% and 18%, respectively. Capillary blood (100 μl) applied on to filter paper was collected on eight occasions during 28 days of follow up. Concentrations of CQ and SDx were determined. A population approach was used for the pharmacokinetic analysis.

RESULTS

A two-compartment model adequately described the data for both CQ and SDx. For CQ, the typical apparent clearance (CL/F) and volume of distribution (V_C/F) values were estimated to be 2.84 l h⁻¹ and 230 l. The typical CL/F for SDx was 0.023 l h⁻¹, while the factor relating its V_C/F to normalized body weight was 1.6 l kg⁻¹. Post hoc parameter estimates for both drugs showed lower maximum concentrations (C_max) and concentration-time curve areas (AUC(0,336 h)) in younger children. The AUC(0,336 h) for SDx and CQ were independently significant factors for prediction of cure. Simulations suggest that giving the higher dose to the youngest children would result in higher CQ and SDx concentrations and improved outcome.

CONCLUSIONS

The study results suggest that full-strength combination to all children would improve the cure rate.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT

• Both chloroquine (CQ) and sulfadoxine/ pyrimethamine (SDx/PYR) remain important drugs in the control of malaria.
• The available data on CQ, SDx and PYR are summary pharmacokinetic parameters based on classical/traditional methods, mostly in adults.
• No study has described the population pharmacokinetics of a fixed-dose CQ + SDx/PYR combination in children with falciparum malaria.

WHAT THIS STUDY ADDS

• This study presents population pharmacokinetic data on CQ and SDx in children with uncomplicated falciparum malaria.
• The study demonstrates that in age-based fixed-dose regimens with CQ and SDx, drug exposures and outcomes may be correctly predicted, although correlation with body weight is poor.
• The study proposes dose modification to improve response with the CQ + SDx/PYR combination.

     

Pharmacokinetic interaction study between benazepril and amlodipine in healthy subjects

Pharmacokinetic interaction between benazepril (ACE inhibitor) and amlodipine (calcium channel blocker) was studied in 12 healthy subjects. Single doses of benazepril hydrochloride (10-mg tablet) and amlodipine besylate (tablet equivalent to 5 mg amlodipine) were administered alone or in combination according to a three-way, Latin-Square, randomized crossover design. Serial blood samples were collected following each administration for the determination of benazepril and its active metabolite benazeprilat and amlodipine. The mean values of AUC (0–4 h), C_max andT _max for benazepril given as combination versus given alone were 161 vs 140 ng·h·ml⁻¹, 168 vs 149 ng·ml⁻¹, and 0.5 vs 0.6 h. The mean values of AUC (0–24 h), C_max andT _max for benazeprilat after benazepril given as combination versus given alone were 1470 vs 1410 ng·h·ml⁻¹, 292 vs 257 ng·ml⁻¹, and 1.7 vs 1.5 h. The mean values of AUC (0–144 h), C_max andT _max for amlodipine given as combination versus given alone were 118 vs 114 ng·h·ml⁻¹, 2.5 vs 2.3 ng·ml⁻¹, and 8.3 vs 9.0 h. The differences in these pharmacokinetic parameters between the combination and monotherapy treatments were not statistically significant based on ANOVA. The results of this study indicate that no pharmacokinetic interaction existed between the two drugs.     

Pharmacokinetic interactions between ciprofloxacin and itraconazole in healthy male volunteers

Objective. To investigate the pharmacokinetic interaction between ciprofloxacin and itraconazole in healthy male volunteers. Methods. Ten healthy male volunteers were assigned into a 2‐sequence, 3‐period pharmacokinetic interaction study. In phase 1, all subjects were randomly assigned to receive 500 mg of ciprofloxacin alone and 200 mg of itraconazole alone twice daily for 7 days with a 14 day wash‐out period in a crossover design. Phase 2 was performed 14 days after finishing phase 1, all subjects received 500 mg of ciprofloxacin in combination with 200 mg of itraconazole twice daily for 7 days. Ciprofloxacin and itraconazole pharmacokinetics were studied and adverse effects noted. Results. Ciprofloxacin significantly increased the C_max and AUC_{0 ? ∞} of itraconazole by 53.13% and 82.46%, respectively. The half‐life and CL of itraconazole were not changed significantly. The combination of itraconazole and ciprofloxacin could therefore result in an increase in adverse drug reactions. Conversely, itraconazole had no significant effect on the pharmacokinetics of ciprofloxacin. Conclusion. Ciprofloxacin decreases the metabolism of itraconazole, most likely through inhibition of CYP3A4. The dosage of itraconazole should be reduced and its therapeutic outcome should be monitored closely when these two agents are concomitantly administered. Copyright © 2011 John Wiley & Sons, Ltd.     

No effect of chloroquine on theophylline pharmacokinetics in the rat

The immediate and delayed effects of chloroquine on theophylline kinetics were investigated in rats pretreated with chloroquine diphosphate (45 mg kg⁻¹) or saline intraperitoneally. One hour or 4 days after chloroquine, theophylline (10 mg kg⁻¹) was administered intravenously. Compared with the control animals pretreated with saline, the disposition parameters of theophylline was not altered after pretreatment with chloroquine. Chloroquine did not affect the in vivo metabolism of theophylline in the laboratory rat. A possible decrease in theophylline's volume of distribution at 4 days, but not immediately, after administration of chloroquine was suggested, although this just failed to achieve statistical significance (p = 0.055). Being marginal, it is unlikely to be of clinical concern. It is concluded that, judged from these animal data, there is no evidence of a drug–drug pharmacokinetic interaction for the combination of chloroquine and theophylline. © 1998 John Wiley & Sons, Ltd.     

Pharmacokinetic investigation of oral and IV dihydroergotamine in healthy subjects

Summary A new radioimmunoassay (RIA) for the specific measurement of dihydroergotamine (DHE), sufficiently sensitive for the determination of low plasma concentrations, has been used to investigate the pharmacokinetics of unchanged DHE. In a randomized crossover trial, eight healthy male volunteers received single doses of DHE 5 mg, 10 mg and 20 mg orally and 0.1 mg and 0.5 mg intravenously. It was possible to determine plasma concentrations and urinary excretion of DHE over the following 48 h. A long terminal plasma elimination phase of unchanged DHE (half-life 15 h) was found. A similar terminal elimination half-life was also calculated from urine data. The multi-exponential decline in plasma DHE with a long terminal half-life suggests that distribution into a deep compartment contributes to the long-lasting effect of the drug. Plasma protein binding was 93%. Despite extensive tissue distribution (V_z=33 l/kg) and a high plasma clearance (CL_P=2l/min), dose-independent linear pharmacokinetics was observed. The present assay was at least 20-times more specific than the polyvalent RIA used previously and appears suitable to explore the pharmacokinetics of unchanged DHE in patients on low-dose therapy. The long terminal elimination half-life of DHE only reported previously in studies using ³H-labelled drug, and considered to be due to metabolites, was also true for the parent compound. This, in addition to the sustained pharmacological activity of the 8-hydroxy metabolite already shown, provides a further explanation for the long duration of action of DHE in animals and man.     

Apparent dose-dependence of chloroquine pharmacokinetics due to limited assay sensitivity and short sampling times

Summary We have shown that apparent nonlinearities in the pharmacokinetics of chloroquine and wide variability in reported kinetic values are possibly artefacts of experimental design. We have used simulated data based on linear equations to demonstrate that chloroquine kinetics may appear to be dose-dependent if samples are collected over a short period or if they are assayed with a method of low sensitivity.     

Pharmacokinetic study of methylnaltrexone after single and multiple subcutaneous administrations in healthy Chinese subjects

1. Pharmacokinetics of methylnaltrexone (MNTX) were evaluated after subcutaneous administrations (s.c.) in healthy Chinese subjects.

2. In a cross-over single dose study, 12 subjects were given 0.075, 0.15, and 0.3?mg/kg of MNTX bromide injection. In a multiple doses study, another 12 subjects subcutaneously received 0.15?mg/kg of MNTX bromide injection every 48?h, in total five administrations. The concentrations of MNTX in plasma were quantified by LC–MS/MS.

3. After single s.c. administrations of 0.075, 0.15, and 0.3?mg/kg of MNTX bromide, C_max values of MNTX were 93.5?±?28.6, 191?±?37, and 364?±?54?ng/mL, respectively, and AUC_0–∞ were 88.8?±?8.8, 181?±?16, and 357?±?34?ng?h/mL, respectively. The t_1/2 of MNTX was about 7.7?h. After multiple doses administration, the C_max, C_av, AUC_ss, and MRT_0–∞ values were 191?±?50, 3.79?±?0.40?ng/mL, 182?±?19?ng?h/mL, and 3.56?±?1.17?h, respectively.

4. Methylnaltrexone bromide displayed dose-proportional pharmacokinetics in the dose range of 0.075–0.3?mg/kg. After multiple doses administration, t_1/2 was slightly prolonged, with the cumulative factor of 1.02. This study provides a pharmacokinetic reference after a single dose and multiple doses of MNTX bromide in Chinese subjects.     

Pharmacokinetic and biopharmaceutic profile of chlordiazepoxide HCl in healthy subjects: Multiple-dose oral administration

Eight healthy male volunteers received chlordiazepoxide HCl orally at a dosage of 10 mg every 8 hr over a period of 21 days. On day 22, the regimen was changed to 30 mg every 24 hr for an additional 15 days. Plasma concentrations of chlordiazepoxide and its metabolites desmethyl-chlordiazepoxide, demoxepam, and desoxydemoxepam were measured during 14 of the 36 treatment days. Chlordiazepoxide plasma concentration- time data were consistent with first-order absorption and complete bioavailability. The harmonic mean absorption half-life was 12.3 min. Disposition of chlordiazepoxide was described by a two-compartment open model with a harmonic mean terminal exponential half-life of 10.1 hr. Average steady — state plasma levels of chlordiazepoxide, desmethylchlordiazepoxide, and demoxepam were approximately 0.75, 0.54, and 0.36 g/ml, respectively.     

Prospects of intermittent preventive treatment of adults against malaria in areas of seasonal and unstable malaria transmission,and a possible role for chloroquine

Chloroquine (CQ) is outmoded as an antimalarial drug in most of the malarial world because of the high resistance rate of parasites. The parasite resistance to CQ is attributed to pfcrt/pfmdr1 gene mutations. Recent studies showed that parasites with mutations of pfcrt/pfmdr1 genes are less virulent, and that those with dhfr/dhps mutations are more susceptible to host immune clearance; the former and latter mutations are linked. In the era of artemisinin-based combination therapy, the frequency of pfcrt/pfmdr1 wild variants is expected to rise. In areas of unstable malaria transmission, the unpredictable severe epidemics of malaria and epidemics of severe malaria could result in high mortality rate among the semi-immune population. With this in mind, the use of CQ for intermittent preventive treatment of adults (IPTa) is suggested as a feasible control measure to reduce malaria mortality in adults and older children without reducing uncomplicated malaria morbidity. The above is discussed in a multidisciplinary approach validating the deployment of molecular techniques in malaria control and showing a possible role for CQ as a rescue drug after being abandoned.     

Pharmacokinetics of amoxicillin coadministered with a saline-polyethylene glycol solution in healthy volunteers

The pharmacokinetics of orally administered amoxicillin were investigated in 12 healthy volunteers in a crossover design. They received either a placebo or a saline—polyethylene glycol solution (SPG) for 4 d, the last dose being given simultaneously with 1 g amoxicillin; blood samples were drawn for the next 12 h. Amoxicillin kinetics were similar in the two treatments but small differences in some pharmacokinetic parameters reached significance. The mean±SD area under the curve was lower with SPG (43.8±6.8 against 47.8±8.2 mg h L^?1, p<0.05) but the treatments were equivalent according to Westlake's test (95% confidence interval = 14.95%). Analysis of SPG against placebo amoxicillin absorption kinetics after fitting the data to a Weibull model revealed a longer duration of the absorption, a slower rate of absorption, and a different shape of the curve. No clinical consequences are expected from these minor variations but possible mechanisms could be relevant to other drugs.     

Halofantrine and chloroquine inhibit CYP2D6 activity in healthy Zambians

AIMS: To determine the effect of therapeutic loading doses of halofantrine and chloroquine on CYP2D6 activity in healthy black Zambians. METHODS: Twenty healthy black male Zambians were phenotyped for CYP2D6 activity by measuring the debrisoquine/4-hydroxydebrisoquine ratio in a 0-8 h urine sample after a 10 mg oral dose of debrisoquine hemi-sulphate. The subjects (all 'extensive metabolizer' phenotype with respect to CYP2D6) were randomized into two groups of 10, and 24 h later one group received 1500 mg halofantrine hydrochloride and the other group 1500 mg chloroquine phosphate both orally in divided doses. All subjects were given further 10 mg doses of debrisoquine at 2 h, 1 week and 2 weeks after the last dose of the antimalarial drug, and phenotyped as described above. RESULTS: The median debrisoquine/4-hydroxydebrisoquine 0-8 h urinary ratio was increased by halofantrine (1.39 to 6.05; P<0.01; 95% confidence intervals 4.00-11.7) and chloroquine (1.96 to 3.91; P<0.01; 95% confidence intervals 1.34-2.66) when debrisoquine was given 2 h after treatment. The decrease in CYP2D6 activity remained statistically significant for 1 week after both drugs. Halofantrine was a significantly more potent inhibitor of CYP2D6 than chloroquine (P=0.037). Phenocopying occurred in two subjects taking halofantrine and one taking chloroquine (i.e. the debrisoquine/4-hydroxydebrisoquine ratios became consistent with the poor metabolizer phenotype). CONCLUSIONS: Given in therapeutic loading doses, both halofantrine and chloroquine caused significant inhibition of CYP2D6 activity in healthy black Zambians. With respect to halofantrine, this finding reinforces the recommendation that its combination with other drugs known to prolong the QT interval should be avoided, especially those that are metabolized significantly by CYP2D6.     

Pharmacokinetic and pharmacodynamic interactions between omeprazole and amoxycillin in Helicobacter pylori-positive healthy subjects.

BACKGROUND: Omeprazole with amoxycillin has been used to treat Helicobacter pylori infection. It was speculated that omeprazole- induced hypoacidity enhances the antibacterial activity of amoxycillin. Limited information exists about intragastric pH and bioavailability of amoxycillin during combination therapy. No data are available about possible effects of the antibiotic on the pharmacokinetics and pharmacodynamics of omeprazole. METHODS: The study was performed in a three-way cross-over double-blind design. After a run-in period on placebo with a baseline intragastric pH-metry, 24 H. pylori-positive healthy subjects were randomly dosed with amoxycillin 750 mg b.d. + placebo, amoxycillin 750 mg b.d. + omeprazole 40 mg b.d. and omeprazole 40 mg b.d. + placebo for 5 days. On the last day of each regimen intragastric pH-metries were performed, and blood samples taken for omeprazole and amoxycillin serum profiles. RESULTS: Amoxycillin monotherapy had no acid-inhibiting effect. Median pH during combined dosing was significantly lower, compared to omeprazole monotherapy (P < 0.01). Mean serum concentrations of omeprazole and amoxycillin given alone or in combination were not different. CONCLUSIONS: High-dose omeprazole does not alter the pharmacokinetics of amoxycillin. The significantly lower intragastric pH during combination therapy might be due to the H. pylori-suppressive effect of this treatment.     

Single dose pharmacokinetics of oral artemether in healthy Malaysian volunteers

Aims To determine the pharmacokinetics of artemether (ARM) and its principal active metabolite, dihydroartemisinin (DHA) in healthy volunteers.
Methods Six healthy male Malaysian subjects were given a single oral dose of 200  mg artemether. Blood samples were collected to 72  h. Plasma concentrations of the two compounds were measured simultaneously by reversed-phase h.p.l.c. with electrochemical detection in the reductive mode.
Results Mean (± s.d.) maximum concentrations of ARM, 310±153  μg  l⁻¹, were reached 1.88±0.21  h after drug intake. The mean elimination half-life was 2.00±0.59  h, and the mean AUC 671±271  μg  l⁻¹ h. The mean C _max of DHA, 273±64  μg  l⁻¹, was observed at 1.92±0.13  h. The mean AUC of DHA was 753±233  μg  h  l⁻¹. ARM and DHA were stable at ≤−20°  C for at least 4 months in plasma samples.
Conclusions The relatively short half-life of ARM may be one of the factors responsible for the poor radical cure rate of falciparum malaria with regimens employing daily dosing. In view of the rapid loss of DHA in plasma samples held at room temperature (26°  C) it is recommended to store them at a temperature of ≤−20°  C as early as possible after sample collection.     

Pharmacokinetics and safety of l-carnitine infused i. v. in healthy subjects

Summary The pharmacokinetics and safety of a brief i. v. infusion of l-carnitine 0, 20, 40 and 60 mg/kg have been investigated in 10 healthy subjects.The diurnal intraindividual variability of plasma carnitine was small (C. V.=3.0, 3.9 and 3.9%, respectively), and the total 24 h excretion in urine was also small and relatively constant: 4.6, 21.5 and 13.0 mg/day in the controls vs 4.6, 20.2 and 6.0 mg/day during treatment in the three subjects to whom saline alone was administered according to a single-blind design. Therefore, the pre-dose level of carnitine was subtracted from the level after dosing for the pharmacokinetic analysis. Plasma carnitine fitted well to a three-compartment open model, with Vc of 0.11–0.20 l/kg and a t_1/2 of 10–23 h. The urine recovery in 24 h was 77.2–95.4%.There were no objective or subjective side-effects attributable to carnitine, so its i. v. infusion is considered to be safe.