The pharmacokinetics of atovaquone and proguanil in pregnant women with acute falciparum malaria

Objective To determine the pharmacokinetic properties of atovaquone, proguanil, and the triazine metabolite cycloguanil in women with recrudescent multi-drug resistant falciparum malaria during the second and third trimesters of pregnancy treated by artesunate-atovaquone-proguanil.Methods Serial plasma concentrations of atovaquone, proguanil and cycloguanil were measured in 24 women at baseline and after the final dose of the 3-day treatment with atovaquone (20 mg/kg/day) plus proguanil (8 mg/kg/day) plus artesunate (4 mg/kg/day) daily.Results The triple combination was well tolerated and highly effective. The outcomes of pregnancy were all normal. Population mean (± SEM) oral clearance (Cl/F) estimates were 313±33 ml/h/kg and 1109±43 ml/h/kg, total apparent volume of distribution (Vd/F) 13.0±1.3 l/kg and 22.9±1.4 l/kg, and terminal elimination half-life; 29.1 h and 14.3 h, for atovaquone and proguanil, respectively. Using conventional and population pharmacokinetic analyses, Cl/F and Vd/F estimates for both drugs were approximately twice, and plasma concentrations less than half those reported previously in healthy subjects and patients with acute malaria.Conclusion Artesunate-atovaquone-proguanil is a promising treatment for multi-drug resistant falciparum malaria during pregnancy, but the dose of atovaquone-proguanil may need to be increased.     

Disposition of oral quinine in acute falciparum malaria

Summary Plasma quinine concentrations following oral quinine sulphate 10 mg salt/kg have been measured by HPLC in 15 adult Thai patients with uncomplicated falciparum malaria. In 10 of the same patients the study was repeated in convalescence. In acute malaria plasma concentrations were approximately 50% higher than in convalescence; the mean acute peak plasma quinine concentration was 8.4 mg·l^–1 compared to 5.7 mg·l^–1 in convalescence.There was considerable variation in the rate of drug absorption, particularly in acute malaria. The mean time to peak plasma concentration was 5.9 h in acute malaria and 3.2 h in convalescence. The apparent clearance of oral quinine (CL/f) during the illness was 1.51 ml·kg^–1·min^–1, which was significantly lower than in convalescence — 2.67 ml·kg^–·min^–1. Estimated free quinine clearance was also lower in the acute phase: 30.6 compared to 49.0 ml·kg^–1·min^–1 in convalescence. Mean (SD) plasma protein binding of quinine was 94.7% in acute malaria and 92.8% in convalescence. Binding was significantly correlated with the plasma concentration of ₁ acid glycoprotein (r=0.5), which was significantly higher in the acute phase; 1.48 g·l^–1 compared to 1.05 g·l^–1 during convalescence.Oral quinine sulphate was well absorbed in uncomplicated falciparum malaria. High blood concentrations following the administration of oral quinine in acute malaria are probably related to increased plasma protein binding, lower apparent volume of distribution, and a reduction in its systemic clearance.     

Population pharmacokinetics of halofantrine in healthy volunteers and patients with symptomatic falciparum malaria

Aims To investigate the population pharmacokinetics of the antimalarial halofantrine (HF) in healthy volunteers and patients with symptomatic falciparum malaria. Methods Healthy volunteer data were obtained from six volunteers who received three different doses of HF (250, 500 and 1000 mg) after an overnight fast with a washout period of at least 6 weeks between doses. Patient data (n = 188) were obtained from randomised controlled trials conducted on the Thai–Burmese border in the early 1990s. They were either assigned to receive a total HF dose of 24 mg/kg (8 mg/kg every 6 h for 24 h) or 72 mg/kg (8 mg/kg every 6 to 10 h for 3 days). The population pharmacokinetics of HF were evaluated using non‐linear mixed effects modelling with a two‐compartment model with first‐order absorption. Key findings The population estimates of apparent clearance (CL), volume of compartment one (V1), distributional clearance (CLD) and volume of compartment two (V2) of HF in healthy volunteers were 2453 l/day (102 l/h), 2386 l, 716 l/day (29.8 l/h) and 2641 l, respectively. The population estimates of the PK parameters in patients were 429 l/day (17.9 l/h), 729 l, 178 l/day (7.42 l/h) and 1351 l, respectively. All PK parameters were significantly related to body weight and some were related to sex, sampling method, pre‐treatment parasite density and whether patients vomited or not. When the two datasets were analysed jointly using a maximum likelihood method, the population estimates in patients were 196 l/day (8.17 l/h), 161 l, 65 l/day (2.71 l/h) and 89 l, respectively, and the parameters were significantly related to body weight and sex. Bayesian analysis of the patient data, with a diffuse prior based on the healthy volunteer data analysis results, yielded the population estimates 354 l/day (14.8 l/h), 728 l, 162 l/day (6.75 l/h) and 1939 l, respectively. Conclusions The pharmacokinetic properties of HF in patients with malaria are affected by several demographic variables as well as other relevant covariates. Apparent differences between the healthy volunteer and the patient data analysis results are not entirely due to differences in bioavailability. For the patient data analysis, the Bayesian method was preferred, as the fitting procedure was more stable, allowing random effects to be estimated for all four dispositional parameters.     

A comparison of the pharmacokinetics of mefloquine in healthy Thai volunteers and in Thai patients with falciparum malaria

Summary We have studied the kinetics of a single oral dose of mefloquine (750 mg) in 12 Thai patients with falciparum malaria and have compared the results with those of a previous study in 12 healthy Thai volunteers [6].All the patients responded to treatment with a mean parasite clearance time of 66.6 h and a mean fever clearance time of 54.1 h.There was no significant difference in peak plasma concentration, time to peak, area under the curve or apparent volume of distribution between patients and controls. However, the terminal half-life (t_1/2) and mean residence time (MRT) were shorter in the patients (12.2 vs 16.7 days for t_1/2 and 15.5 vs 21.4 days for MRT).We conclude that there are changes in the disposition of mefloquine related to malaria, although the exact basis of the changes is not clear.     

Clinical efficacy and pharmacokinetics of artemisinin monotherapy and in combination with mefloquine in patients with falciparum malaria

1The aim of this study was to assess the pharmacokinetics, clinical efficacy and safety of artemisinin alone and in combination with mefloquine. 2Thirty-eight adults with symptomatic Plasmodium falciparum malaria were randomly assigned to receive either artemisinin (500 mg single dose followed by another 500 mg on day 1 and then 250 mg twice daily for 4 days) or artemisinin (500 mg single dose followed by 750 mg on day 1 and then 250 mg three times daily for one more day) in co-administration with mefloquine (250 mg three times daily for the first day). All drug administration was by the oral route. Patients were hospitalized at the Kibaha Designated District Hospital, Kibaha, Tanzania, for 6 days and a follow up for 3 weeks was performed. 3Treatment with the artemisinin/mefloquine combination resulted in a shorter parasite clearance time (PCT) of 24 (22, 27; 95% confidence interval) h vs 31 (27, 36) h and fever subsidence time (FST) of 14 (12, 16) h vs 20 (18, 23) h compared with artemisinin monotherapy. The 95% CI for the difference of the PCT and FST were 1.7, 12 and 3, 10, respectively. Parasites were detected in 7 out of 17 patients (41%) receiving artemisinin monotherapy at the 3rd and 4th week follow up visits. No parasites were detected after the combination therapy. 4The maximum plasma concentrations ( C_max) were similar after artemisinin monotherapy (615.4±387.0 ng ml⁻¹) and in combination with mefloquine (851.8±523.6 ng ml⁻¹). Elimination half-lives (t_1/2) were also identical at 2.2±0.6 h and 2.5±0.7 h, respectively. However, the AUC values were higher ( P<0.05) after combination therapy (3252±1873 ng  ml⁻¹ h) than after monotherapy (2234±1502 ng ml⁻¹ h). The oral clearance values were lower ( P<0.05) after combination therapy (195.4±86.9 l h⁻¹) than after monotherapy (314.3±189.4 l h⁻¹). PCT and FST normalized to initial parasitaemia correlated with AUC(0,  t) (r_s=0.56, P=0.02, r_s=0.58, P=0.01, respectively) and with C_max (r_s=0.62, P=0.01, r_s=0.68, P=0.005, respectively) in the artemisinin monotherapy only. 5One patient on the combination therapy developed a psychiatric condition and two patients on the monotherapy developed skin itch.     

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.     

Pharmacokinetics of quinine in African patients with acute falciparum malaria.

The pharmacokinetics of quinine were studied in six Nigerian patients during acute uncomplicated falciparum malaria and convalescent periods. An oral dose of 10 mg/kg quinine dihydrochloride administered 8hourly for 7 days gave parasite and fever clearance times of 36.0 ± 16.6 h and 18.0 ± 6.4 h, respectively. From the individual quinine plasma profiles the mean plasma concentration of quinine at the time of parasite clearance was estimated as 4.5 ± 1.1 g/ml. Plasma quinine levels during malaria rose rapidly reaching a peak around the second and third days and declining thereafter as patients improved clinically. In acute malaria plasma quinine levels were more than two-fold higher than in convalescence; the mean AUC(0-12) in malaria was 37.9 ± 14.7 g.h/ml compared to 17.9 ± 8.5g.h/ml in convalescence. The apparent oral clearance (CL/F) and volume of distribution (Vd/F) duri ng the acute phase of the malaria (1.9 ± 0.7 ml/min/kg and 1.8 ± 0.9 l/kg, respectively) were significantly lower than in convalescence (4.5 ± 2.1 ml/min/kg and 4.2 ± 3.2 l/kg). The present data suggest that malaria parasites in African patients are still very sensitive to quinine and that the current dosage of quinine is effective for the treatment of acute falciparum malaria in African patients without augmenting therapy with any other drug such as tetracycline or sulphadoxine-pyrimethamine. It also confirms that malaria significantly alters the pharmacokinetics of quinine in humans.     

老年心衰患者口服地高辛群体药动学模型的建立

目的:应用非线性混合效应模型计算国人老年心衰患者口服地高辛(digxion)群体药动学参数,以促进个体化给药。方法:采用荧光偏振免疫法(FPIA)测定84例老年患者120例次地高辛的血清浓度并收集相关临床指标,运用NONMEM软件建立群体药动学模型。结果:地高辛的药动学符合一室线性开放模型,固定效应参数中,体质量、剂量、血肌酐及尿素氮对参数有影响。最终回归模型中地高辛血药浓度估算值与实测浓度间线性关系良好。结论:用群体药动学模型分析常规监测数据可为老年患者个体化给药提供依据。     

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.

     

Efficacy and pharmacokinetics of a new intrarectal quinine formulation in children with Plasmodium falciparum malaria

1Three groups of seven children aged 2–14 years with acute uncomplicated Plasmodium falciparum malaria received 12.8 mg kg⁻¹ quinine gluconate by the intrarectal route (new cream formulation) or 8 mg kg⁻¹ Quinimax (a Cinchona alkaloid combination) by the intramuscular or intravenous (4 h infusion) route every 8 h for 3 days. Clinical and parasitological status was similar in the three groups at enrolment. 2At 36 h, body temperature of all children of the three groups was returned to normal and remained so until day 7. 3The decrease in parasitaemia did not differ between the three groups and the time required for a 50% fall in parasitaemia relative to baseline was 12.3±5.4, 18.2±6.1 and 14.5±4.2 h in the intrarectal, intramuscular and intravenous treatment groups, respectively. Parasitaemia expressed as a percentage of initial values was not significantly different in the three groups after 48 h of treatment (7.4±16.0, 4.1±4.2 and 2.2±3.8% in the intrarectal, intramuscular and intravenous treatment groups, respectively). All the patients were aparasitaemic by day 7. 4The tolerability of the three treatments was good; in particular, no rectal irritation was reported with the cream formulation. 5The t_max occurred later after intrarectal (4.1±2.4 h) and intravenous infusion (3.8±0.5 h) than after intramuscular injection (1.6±1.3 h) (P=0.02). C_max was lower with the intrarectal (3.0±1.0 mg l⁻¹) and intramuscular routes (3.2±0.7 mg l⁻¹) than with the intravenous route (5.1±1.4 mg l⁻¹) (P=0.003). Areas under the curve (AUC(0, 8 h)) were smaller with the intrarectal (17.0±7 mg l⁻¹ h) and intramuscular routes (19.4±4.8 mg l⁻¹ h) than with the intravenous route (27.8±8.2 mg l⁻¹ h) (P=0.02). The approximate bioavailability of intrarectal quinine from 0 to 8 h was 36%vs intravenous quinine and 51%vs intramuscular quinine. 6The good tolerability and efficacy of this new intrarectal quinine formulation outweigh its low approximate bioavailability. This new approach might thus be a safe and effective alternative to intramuscular quinine injection for the treatment of children with acute uncomplicated Plasmodium falciparum malaria in the field.     

Population pharmacokinetics of artemether and dihydroartemisinin following single intramuscular dosing of artemether in African children with severe falciparum malaria

AIMS: To determine the population pharmacokinetics of artemether and dihydroartemisinin in African children with severe malaria and acidosis associated with respiratory distress following an intramuscular injection of artemether. METHODS: Following a single intramuscular (i.m.) injection of 3.2 mg kg-1 artemether, blood samples were withdrawn at various times over 24 h after the dose. Plasma was assayed for artemether and dihydroartemisinin by gas chromatography-mass spectrometry. The software program NONMEM was used to fit the concentration-time data and investigate the influence of a range of clinical characteristics (respiratory distress and metabolic acidosis, demographic features and disease) on the pharmacokinetics of artemether and dihydroartemisinin. RESULTS: A total of 100 children with a median age of 36.4 (range 5-108) months were recruited into the study and data from 90 of these children (30 with respiratory distress and 60 with no respiratory distress) were used in the population pharmacokinetic analysis. The best model to describe the disposition of artemether was a one-compartment model with first-order absorption and elimination. The population estimate of clearance (clearance/bioavailability, CL/F) was 14.3 l h-1 with 53% intersubject variability and that of the terminal half-life was 18.5 h. If it was assumed that artemisin displays "flip-flop" kinetics, the elimination half-life was estimated to be 21 min and the corresponding volume of distribution was 8.44 l, with an intersubject variability of 104%. None of the covariates could be identified as having any influence on the disposition of artemether. The disposition of dihydroartemisinin was fitted separately using a one-compartment linear model in which the volume of distribution was fixed to the same value as that of artemether. Assuming that artemether is completely converted to dihydroartemisinin, the estimated value of CL/F for dihydroartemisinin was 93.5 l h-1, with an intersubject variability of 90.2%. The clearance of dihydroartemisinin was formation rate limited. CONCLUSIONS: Administration of a single 3.2 mg kg-1 i.m. dose of artemether to African children with severe malaria and acidosis is characterized by variable absorption kinetics, probably related to drug formulation characteristics rather than to pathophysiological factors. Use of i.m. artemether in such children needs to be reconsidered.     

Population pharmacokinetics of levosimendan in patients with congestive heart failure

AIMS: The aim of this study was to characterize the population pharmacokinetics of levosimendan in patients with heart failure (NYHA grades III and IV) and its relationship to demographic factors, disease severity and concomitant use of digoxin and beta-blocking agents. METHODS: Data from two efficacy studies with levosimendan administered by intravenous infusion were combined (190 patients in total). The data were analysed using a nonlinear mixed-effects modelling approach as implemented in the NONMEM program. The model development was done in three sequential steps. First the best structural model was determined (e.g. a one-, two- or three-compartment pharmacokinetic model). This was followed by the identification and incorporation of important covariates into the model. Lastly the stochastic part of the model was refined. RESULTS: A two-compartment model best described levosimendan pharmacokinetics. Clearance and the central volume of distribution were found to increase linearly with bodyweight. No other covariates, including concomitant use of digoxin and beta-blocking agents, influenced the pharmacokinetics. In the final model, a 76-kg patient was estimated to have a clearance +/- s.e. of 13.3 +/- 0.4 l h-1 and a central volume of distribution of 16.8 +/- 0.79 l. The interindividual variability was estimated to be 39% and 60% for clearance and central volume of distribution, respectively. Weight changed clearance by 1.5% [95% confidence interval (CI) 0.9%, 2.1%] and the central volume of distribution by 0.9% (95% CI 0.5%, 1.3%) per kg. CONCLUSIONS: The population pharmacokinetics parameters of levosimendan in this patient group were comparable to those obtained by traditional methods in healthy volunteers and patients with mild heart failure. Bodyweight influenced the clearance and the central volume of distribution, which in practice is accounted for by weight adjusting doses. None of the other covariates, including digoxin and beta-blocking agents, significantly influenced the pharmacokinetics of levosimendan.     

Population pharmacokinetics of darbepoetin alfa in haemodialysis and peritoneal dialysis patients after intravenous administration

AIMS: To characterize the pharmacokinetics of darbepoetin alfa and covariate relationships in haemodialysis (HD) and peritoneal dialysis (PD) patients. METHODS: Data were collected from 131 (63 HD and 68 PD) patients who received darbepoetin alfa intravenously. A total of 917 serum concentrations were available. The data were analysed by nonlinear mixed effect modelling using NONMEM with a model including endogenous erythropoietin production. In addition, the final model was evaluated using bootstrap resampling. RESULTS: The selected basic model was a two-compartment model with a combination of additive and the constant coefficient of variation error models. The significant covariates were weight (WT) for clearance (CL) and the volume of central compartment (V(1)), and the dialysis technique (DIA) for V(1). The typical values of CL and V(1) were 0.0807 l h(-1) and 2.51 l, respectively. V(1) in PD patients was 17% higher than in HD patients. With the introduction of WT in CL and WT and DIA in V(1), interindividual variability decreased from 27.1% to 20.6% in CL and from 29.1% to 21.8% in V(1). The mean parameter estimates from the bootstrap datasets were similar to those from the original dataset. Evaluation by bootstrapping showed that the final model was stable. CONCLUSIONS: The results of the present analysis suggest no dosage regimen change is warranted for darbepoetin alfa in HD and PD patients over the range of distribution of covariates included in this study.     

The pharmacokinetics and pharmacodynamics of atovaquone and proguanil for the treatment of uncomplicated falciparum malaria in third-trimester pregnant women

OBJECTIVE: To investigate the pharmacokinetics, safety and efficacy of the recommended 3-day treatment regimen of Malarone in third-trimester pregnant women with acute uncomplicated falciparum malaria. METHODS: Twenty-six pregnant women in their third trimester (gestational age: 24–34 weeks) with acute uncomplicated Plasmodium falciparum malaria who fulfilled the enrollment criteria were recruited from the antenatal clinics of Mae Sot Hospital, Tak Province, Thailand, (n=8) and the Tropical Diseases Research Centre, Ndola, Zambia (n=18). Patients were treated with four Malarone tablets (GlaxoSmithKline: each tablet contains 250 mg atovaquone and 100 mg proguanil) once daily for 3 consecutive days. Blood samples were taken for pharmacokinetic investigations of atovaquone, proguanil, and cycloguanil up to 288 h (day 14) after the last dose. Urine samples were collected for the evaluation of proguanil and cycloguanil 0–8, 8–16, 16–24 and 24–48 h after the last dose. Efficacy assessments included the clinical and parasitological evaluation of mothers and newborns. Adverse events were evaluated at each visit to the antenatal clinics. RESULTS: Malarone appeared to be effective and well tolerated when used for the treatment of falciparum malaria in pregnant women. All patients showed prompt clinical improvement and the disappearance of parasitaemia after treatment. There were no serious adverse effects or unexpected adverse effects and no stillbirths or spontaneous abortions. The plasma concentration-time profiles of atovaquone and proguanil in most cases were best characterised by the two-compartment open model with zero-order input with/without absorption lag time and first-order elimination. There were no significant differences in any of the pharmacokinetic parameters of atovaquone, proguanil or cycloguanil between patients from Thailand and Zambia. For atovaquone, a C_max of 1.33–8.33 g/ml was reached at 2.0–9.3 h after the last dose on day 2. V/F, CL/F and t_1/2 were 6.9–39.5 l/kg, 83–384 ml/h/kg, and 57.8–130.8 h, respectively. The C_max and t_max values for proguanil versus cycloguanil were 383–918 versus 0–129 ng/ml and 3.3–8.6 versus 3–12 h, respectively. V/F, CL/F, and t_1/2 values for proguanil were 10.7–34.0 l/kg, 431–1,662 ml/h/kg and 11.2–30.3 h. The CL_R-CG, t_1/2z, _CG, proguanil/cycloguanil metabolic ratios, AUC ratios for proguanil to cycloguanil (AUC_PG/CG) were 107.2–1,001 ml/h/kg, 5–95 ml/h/kg, 7.8–20.7 h, 5–57, and 4.7–20.2, respectively. CONCLUSION: The pharmacokinetics of atovaquone and cycloguanil appeared to be influenced by the pregnancy status, resulting in an decrease in the C_max and AUC of approximately twofold.     

用NONMEM法建立西酞普兰群体药代动力学模型

目的建立中国人西酞普兰(抗抑郁药)的群体药代动力学(PPK)模型,为临床个体化给药提供参考。方法用群体药代动力学方法,对西酞普兰生物等效性研究中23例受试者的血药浓度和临床资料进行分析,用NON-MEM软件求算西酞普兰的PPK参数值,建立西酞普兰的PPK模型,并进行模型验证。结果经NONMEM法处理,所有因素中,年龄、体重以及CYP2C19基因型对中央隔室清除率有显著性的影响;体重对分布容积有显著性的影响。年龄和体重的增加对清除率影响分别为-0.39L·h-1.a-1和0.18L.h-1·kg-1。结论用NONMEM软件拟合获得的西酞普兰群体药代动力学最终模型,经验证稳定可靠。     

Population pharmacokinetics of oral diclofenac for acute pain in children

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT

• Diclofenac is an effective oral analgesic for acute postoperative pain. In adults 25 mg is half as effective as 50 mg, but 50 mg and 100 mg are similarly effective (ceiling effect). Diclofenac has linear pharmacokinetics in this range.
• Diclofenac is frequently used ‘off-label’ in children for acute pain but optimum dosing is unclear (dosing of diclofenac in clinical paediatric studies ranges from 0.5–2.5 mg kg⁻¹). There is currently no licensed oral paediatric formulation of diclofenac.

WHAT THIS STUDY ADDS

• Using a new diclofenac oral suspension, a dose of 1 mg kg⁻¹ in children aged 1 to 12 years gives a similar exposure to 50 mg in adults; paediatric patients are unlikely to benefit from higher doses.

AIMS

To develop a population pharmacokinetic model for a new diclofenac suspension (50 mg 5 ml⁻¹) in adult volunteers and paediatric patients, and recommend a dose for acute pain in children.

METHODS

Blood samples were drawn at the start and end of surgery, and on removal of the venous cannula from 70 children (aged 1 to 12 years, weight 9 to 37 kg) who received a preoperative oral 1 mg kg⁻¹ dose; these were pooled with rich (14 post-dose samples) data from 30 adult volunteers. Population pharmacokinetic modelling was undertaken with NONMEM. The optimum adult dose of diclofenac for acute pain is 50 mg. Simulation from the final model was performed to predict a paediatric dose to achieve a similar AUC to 50 mg in adults.

RESULTS

A total of 558 serum diclofenac concentrations from 100 subjects was used in the pooled analysis. A single disposition compartment model with first order elimination and dual absorption compartments was used. The estimates of CL/F and V_D/F were 53.98 l h⁻¹ 70 kg⁻¹ and 4.84 l 70 kg⁻¹ respectively. Allometric size models appeared to predict adequately changes in CL and V_D with age. Of the simulated doses investigated, 1 mg kg⁻¹ gave paediatric AUC_{(0, 12 h)} to adult 50 mg AUC_{(0, 12 h)} ratios of 1.00, 1.08 and 1.18 for ages 1–3, 4–6 and 7–12 years respectively.

CONCLUSIONS

This study has shown 1 mg kg⁻¹ diclofenac to produce similar exposure in children aged 1 to 12 years as 50 mg in adults, and is acceptable for clinical practice; patients are unlikely to obtain further benefit from higher doses.     

Population pharmacokinetics of tamsulosin hydrochloride in paediatric patients with neuropathic and non-neuropathic bladder

AIMS

The main objective of this study was to characterize the population pharmacokinetics of tamsulosin hydrochloride (HCl) in paediatric patients with neuropathic and non-neuropathic bladder. A secondary objective was to compare the pharmacokinetics in paediatric patients and adults.

METHODS

Tamsulosin HCl plasma concentrations in 1082 plasma samples from 189 paediatric patients (age range 2–16 years) were analyzed with NONMEM, applying a one compartment model with first-order absorption. Based on the principles of allometry, body weight was incorporated in the base model, along with fixed allometric exponents. Covariate analysis was performed by means of a stepwise forward inclusion and backward elimination procedure. Simulations based on the final model were used to compare the pharmacokinetics with those in adults.

RESULTS

Beside the priori-implemented body weight, only α₁-acid glycoprotein had an effect on both apparent clearance and apparent volume of distribution. No other investigated covariates, including gender, age, race, patient population and concomitant therapy with anti-cholinergics, significantly affected the pharmacokinetics of tamsulosin HCl (P < 0.001). The results of simulations indicated that the exposure in 12.5 kg paediatric patients was 3.5–4.3 fold higher than that in 70.0 kg adults. After a weight-based dose administration, the exposure in paediatric patients was comparable with that in healthy adults.

CONCLUSIONS

A population pharmacokinetic model of tamsulosin HCl in paediatric patients was established and it described the data well. There was no major difference in the pharmacokinetics of tamsulosin HCl between paediatric patients (age range 2–16 years) and adults when the effect of body weight was taken into consideration.