scholarly journals Pharmacokinetics of Dihydroartemisinin and Piperaquine in Pregnant and Nonpregnant Women with Uncomplicated Falciparum Malaria

2011 ◽  
Vol 55 (12) ◽  
pp. 5500-5506 ◽  
Author(s):  
Marcus J. Rijken ◽  
Rose McGready ◽  
Aung Phae Phyo ◽  
Niklas Lindegardh ◽  
Joel Tarning ◽  
...  
Keyword(s):  
Pregnant Women ◽  
Falciparum Malaria ◽  
Half Life ◽  
Drug Exposure ◽  
Venous Blood ◽  
Uncomplicated Falciparum Malaria ◽  
Fixed Dose ◽  
Pharmacokinetic Parameters ◽  
Population Pharmacokinetic ◽  
Population Pharmacokinetic Modeling

ABSTRACTDihydroartemisinin-piperaquine is a fixed-dose artemisinin-based combination treatment. Some antimalarials have altered pharmacokinetics in pregnancy. Pregnant women in the 2nd or 3rd trimester and matched nonpregnant women with uncomplicated falciparum malaria were treated with a total of 6.4 mg/kg of body weight dihydroartemisinin and 51.2 mg/kg piperaquine once daily for 3 days. Venous blood samples were drawn at prespecified time points over 9 weeks. Plasma dihydroartemisinin and piperaquine concentrations were analyzed by liquid chromatography-mass spectrometry. Piperaquine and dihydroartemisinin pharmacokinetics were well described. There were no significant differences in total piperaquine exposure (P= 0.80) or drug exposure during the terminal elimination phase (72 h to infinity) (P= 0.64) between the two groups. The apparent volume of distribution of piperaquine was significantly smaller (602 liters/kg versus 877 liters/kg) in pregnant women than in nonpregnant women (P= 0.0057), and the terminal elimination half-life was significantly shorter (17.8 days versus 25.6 days;P= 0.0023). Dihydroartemisinin exposure after the first dose was significantly lower (844 h × ng/ml versus 1,220 h × ng/ml,P= 0.0021) in pregnant women, but there were no significant differences in total dihydroartemisinin exposure or maximum concentrations between the two groups. There were no significant differences in any pharmacokinetic parameters between the second and third trimester. These results obtained through noncompartmental analysis suggest that in the treatment of falciparum malaria, there are no clinically important differences in the pharmacokinetics of dihydroartemisinin or piperaquine between pregnant and nonpregnant women. However, a more detailed analysis using population pharmacokinetic modeling is needed to fully investigate the differences found for some of the pharmacokinetic parameters, such as the terminal half-life.

scholarly journals Pharmacokinetic profile of amodiaquine and its active metabolite desethylamodiaquine in Ghanaian patients with uncomplicated falciparum malaria

2021 ◽  
Vol 20 (1) ◽  
Author(s):  
Thomas A. Anyorigiya ◽  
Sandra Castel ◽  
Katya Mauff ◽  
Frank Atuguba ◽  
Bernhards Ogutu ◽  
...  
Keyword(s):  
Falciparum Malaria ◽  
Active Metabolite ◽  
Drug Exposure ◽  
Age Groups ◽  
Uncomplicated Falciparum Malaria ◽  
Fixed Dose ◽  
Pharmacokinetic Analysis ◽  
Pharmacokinetic Parameters ◽  
Close Monitoring ◽  
Drug Concentrations

Abstract Background Accurate measurement of anti-malarial drug concentrations in therapeutic efficacy studies is essential to distinguish between inadequate drug exposure and anti-malarial drug resistance, and to inform optimal anti-malarial dosing in key target population groups. Methods A sensitive and selective LC–MS/MS method was developed and validated for the simultaneous determination of amodiaquine and its active metabolite, desethylamodiaquine, and used to describe their pharmacokinetic parameters in Ghanaian patients with uncomplicated falciparum malaria treated with the fixed-dose combination, artesunate-amodiaquine. Results The day-28 genotype-adjusted adequate clinical and parasitological response rate in 308 patients studied was > 97% by both intention-to-treat and per-protocol analysis. After excluding 64 patients with quantifiable amodiaquine concentrations pre-treatment and 17 with too few quantifiable concentrations, the pharmacokinetic analysis included 227 patients (9 infants, 127 aged 1–4 years, 91 aged ≥ 5 years). Increased median day-3 amodiaquine concentrations were associated with a lower risk of treatment failure [HR 0.87 (95% CI 0.78–0.98), p = 0.021]. Amodiaquine exposure (median AUC0-∞) was significantly higher in infants (4201 ng h/mL) and children aged 1–5 years (1994 ng h/mL) compared to older children and adults (875 ng h/mL, p = 0.001), even though infants received a lower mg/kg amodiaquine dose (median 25.3 versus 33.8 mg/kg in older patients). Desethylamodiaquine AUC0-∞ was not significantly associated with age. No significant safety concerns were identified. Conclusions Efficacy of artesunate-amodiaquine at currently recommended dosage regimens was high across all age groups. Reassuringly, amodiaquine and desethylamodiaquine exposure was not reduced in underweight-for-age young children or those with high parasitaemia, two of the most vulnerable target populations. A larger pharmacokinetic study with close monitoring of safety, including full blood counts and liver function tests, is needed to confirm the higher amodiaquine exposure in infants, understand any safety implications and assess whether dose optimization in this vulnerable, understudied population is needed.

scholarly journals Validation and Pharmacokinetic Application of a High-Performance Liquid Chromatographic Technique for Determining the Concentrations of Amodiaquine and Its Metabolite in Plasma of Patients Treated with Oral Fixed-Dose Amodiaquine-Artesunate Combination in Areas of Malaria Endemicity

2015 ◽  
Vol 59 (9) ◽  
pp. 5114-5122 ◽  
Author(s):  
Olumuyiwa N. Adedeji ◽  
Oluseye O. Bolaji ◽  
Catherine O. Falade ◽  
Odusoga A. Osonuga ◽  
Olusegun G. Ademowo
Keyword(s):  
Falciparum Malaria ◽  
High Performance ◽  
Limit Of Detection ◽  
Clinical Success ◽  
Plasma Concentrations ◽  
Uncomplicated Falciparum Malaria ◽  
Fixed Dose ◽  
Pharmacokinetic Parameters ◽  
Maximum Plasma ◽  
Chromatographic Technique

ABSTRACTArtemisinin-based combination therapies (ACTs) have been adopted by most African countries, including Nigeria, as first-line treatments for uncomplicated falciparum malaria. Fixed-dose combinations of these ACTs, amodiaquine-artesunate (FDC AQAS) and artemether-lumefantrine (AL), were introduced in Nigeria to improve compliance and achieve positive outcomes of malaria treatment. In order to achieve clinical success with AQAS, we developed and validated a simple and sensitive high-performance liquid chromatography (HPLC) method with UV detection for determination of amodiaquine (AQ) and desethylamodiaquine (DAQ) in plasma using liquid-liquid extraction of the drugs with diethyl ether following protein precipitation with acetonitrile. Chromatographic separation was achieved using an Agilent Zorbax C18column and a mobile phase consisting of distilled water-methanol (80:20 [vol/vol]) with 2% (vol/vol) triethylamine, pH 2.2, at a flow rate of 1 ml/min. Calibration curves in spiked plasma were linear from 100 to 1,000 ng/ml (r> 0.99) for both AQ and DAQ. The limit of detection was 1 ng (sample size, 20 μl). The intra- and interday coefficients of variation at 150, 300, and 900 ng/ml ranged from 1.3 to 4.8%, and the biases were between 6.4 and 9.5%. The mean extraction recoveries of AQ and DAQ were 80.0% and 68.9%, respectively. The results for the pharmacokinetic parameters of DAQ following oral administration of FDC AQAS (612/200 mg) for 3 days in female and male patients with uncomplicated falciparum malaria showed that the maximum plasma concentrations (Cmax) (740 ± 197 versus 767 ± 185 ng/ml), areas under the plasma concentration-time curve (AUC) (185,080 ± 20,813 versus 184,940 ± 16,370 h · ng/ml), and elimination half-life values (T1/2) (212 ± 1.14 versus 214 ± 0.84 h) were similar (P> 0.05).

scholarly journals Low Antituberculosis Drug Concentrations in HIV-Tuberculosis-Coinfected Adults with Low Body Weight: Is It Time To Update Dosing Guidelines?

2019 ◽  
Vol 63 (6) ◽  
Author(s):  
Christine Sekaggya-Wiltshire ◽  
Maxwell Chirehwa ◽  
Joseph Musaazi ◽  
Amrei von Braun ◽  
Allan Buzibye ◽  
...  
Keyword(s):  
Drug Exposure ◽  
Fixed Dose ◽  
Population Pharmacokinetic ◽  
Population Pharmacokinetic Modeling ◽  
Drug Concentrations ◽  
Optimal Drug ◽  
Lower Drug ◽  
Dose Combination ◽  
Current Weight

ABSTRACT Antituberculosis drugs display large pharmacokinetic variability, which may be influenced by several factors, including body size, genetic differences, and drug-drug interactions. We set out to determine these factors, quantify their effect, and determine the dose adjustments necessary for optimal drug concentrations. HIV-infected Ugandan adults with pulmonary tuberculosis treated according to international weight-based dosing guidelines underwent pharmacokinetic sampling (1, 2, and 4 h after drug intake) 2, 8, and 24 weeks after treatment initiation. Between May 2013 and November 2015, we enrolled 268 patients (148 males) with a median weight of 53.5 (interquartile range [IQR], 47.5 to 59.0) kg and a median age of 35 (IQR, 29 to 40) years. Population pharmacokinetic modeling was used to interpret the data and revealed that patients weighing <55 kg achieved lower concentrations than those in higher weight bands for all drugs in the regimen. The models predicted that this imbalance could be solved with a dose increment of one fixed-dose combination (FDC) tablet for the weight bands of 30 to 37 and 38 to 54 kg. Additionally, the concomitant use of efavirenz increased isoniazid clearance by 24.1%, while bioavailability and absorption of rifampin and isoniazid varied up to 30% in patients on different formulations. Current dosing guidelines lead to lower drug exposure in patients in the lower weight bands. Simply adding one FDC tablet to current weight band-based dosing would address these differences in exposure and possibly improve outcomes. Lower isoniazid exposures due to efavirenz deserve further attention, as does the quality of currently used drug formulations of anti-TB drugs. (This study has been registered at ClinicalTrials.gov under identifier NCT01782950.)

scholarly journals Optimal Antimalarial Dose Regimens for Sulfadoxine-Pyrimethamine with or without Azithromycin in Pregnancy Based on Population Pharmacokinetic Modeling

2017 ◽  
Vol 61 (5) ◽  
Author(s):  
Sam Salman ◽  
Francisca Baiwog ◽  
Madhu Page-Sharp ◽  
Susan Griffin ◽  
Harin A. Karunajeewa ◽  
...  
Keyword(s):  
Pregnant Women ◽  
Drug Exposure ◽  
Intermittent Preventive Treatment ◽  
Preventive Treatment ◽  
Population Pharmacokinetic ◽  
Time Data ◽  
Mixed Effect ◽  
Population Pharmacokinetic Modeling ◽  
Final Population ◽  
In Pregnancy

ABSTRACT Optimal dosing of sulfadoxine-pyrimethamine (SP) as intermittent preventive treatment in pregnancy remains to be established, particularly when coadministered with azithromycin (AZI). To further characterize SP pharmacokinetics in pregnancy, plasma concentration-time data from 45 nonpregnant and 45 pregnant women treated with SP-AZI (n = 15 in each group) and SP-chloroquine (n = 30 in each group) were analyzed. Population nonlinear mixed-effect pharmacokinetic models were developed for pyrimethamine (PYR), sulfadoxine (SDOX), and N-acetylsulfadoxine (the SDOX metabolite NASDOX), and potential covariates were included. Pregnancy increased the relative clearance (CL/F) of PYR, SDOX, and NASDOX by 48, 29, and 70%, respectively, as well as the relative volumes of distribution (V/F) of PYR (46 and 99%) and NASDOX (46%). Coadministration of AZI resulted in a greater increase in PYR CL/F (80%) and also increased NASDOX V/F by 76%. Apparent differences between these results and those of published studies of SP disposition may reflect key differences in study design, including the use of an early postpartum follow-up study rather than a nonpregnant comparator group. Simulations based on the final population model demonstrated that, compared to conventional single-dose SP in nonpregnant women, two such doses given 24 h apart should ensure that pregnant women have similar drug exposure, while three daily SP doses may be required if SP is given with AZI. The results of past and ongoing trials using recommended adult SP doses with or without AZI in pregnant women may need to be interpreted in light of these findings and consideration given to using increased doses in future trials.

scholarly journals Steady-State Plasma and Intrapulmonary Pharmacokinetics and Pharmacodynamics of Cethromycin

2004 ◽  
Vol 48 (9) ◽  
pp. 3508-3515 ◽  
Author(s):  
John E. Conte ◽  
Jeffrey A. Golden ◽  
Juliana Kipps ◽  
Elisabeth Zurlinden
Keyword(s):  
Steady State ◽  
Half Life ◽  
Dose Group ◽  
Drug Exposure ◽  
Pharmacokinetic Parameters ◽  
Multiple Time ◽  
Respiratory Pathogens ◽  
Once Daily ◽  
Standard Deviations ◽  
State Plasma

ABSTRACT The objective of this study was to determine the steady-state plasma and intrapulmonary pharmacokinetic parameters of orally administered cethromycin in healthy volunteers. The study design included administering 150 or 300 mg of cethromycin once daily to 25 or 35 healthy adult subjects, respectively, for a total of five doses. Standardized and timed bronchoalveolar lavage (BAL) was performed after the last dose. Blood was obtained for drug assay prior to the first and last dose, at multiple time points following the last dose, and at the time of BAL. Cethromycin was measured in plasma, BAL, and alveolar cell (AC) by using a combined high-performance liquid chromatography-mass spectrometric technique. Plasma, epithelial lining fluid (ELF), and AC pharmacokinetics were derived by noncompartmental methods. C max/90% minimum inhibitory concentration (MIC90) ratios, area under the concentration-time curve (AUC)/MIC90 ratios, intrapulmonary drug exposure ratios, and percent time above MIC90 during the dosing interval (%T > MIC90) were calculated for recently reported respiratory pathogens. The kinetics were nonlinear, i.e., not proportional to dose. In the 150-mg-dose group, the C max (mean ± standard deviations), AUC0-24, and half-life for plasma were 0.181 ± 0.084 μg/ml, 0.902 ± 0.469 μg · h/ml, and 4.85 ± 1.10 h, respectively; for ELF the values were 0.9 ± 0.2 μg/ml, 11.4 μg · h/ml, and 6.43 h, respectively; for AC the values were 12.7 ± 6.4 μg/ml, 160.8 μg · h/ml, and 10.0 h, respectively. In the 300-mg-dose group, the C max (mean ± standard deviations), AUC0-24, and half-life for plasma were 0.500 ± 0.168 μg/ml, 3.067 ± 1.205 μg · h/ml, and 4.94 ± 0.66 h, respectively; for ELF the values were 2.7 ± 2.0 μg/ml, 24.15 μg · h/ml, and 5.26 h, respectively; for AC the values were 55.4 ± 38.7 μg/ml, 636.2 μg · h/ml, and 11.6 h, respectively. We concluded that the C max/MIC90 ratios, AUC/MIC90 ratios, %T > MIC90 values, and extended plasma and intrapulmonary half-lives provide a pharmacokinetic rationale for once-daily administration and are favorable for the treatment of cethromycin-susceptible pulmonary infections.

The pharmacokinetics of artemether and lumefantrine in pregnant women with uncomplicated falciparum malaria

2006 ◽  
Vol 62 (12) ◽  
pp. 1021-1031 ◽  
Author(s):  
Rose McGready ◽  
Kasia Stepniewska ◽  
Niklas Lindegardh ◽  
Elizabeth A. Ashley ◽  
Yar La ◽  
...  
Keyword(s):  
Pregnant Women ◽  
Falciparum Malaria ◽  
Uncomplicated Falciparum Malaria

scholarly journals Population Pharmacokinetics of Atazanavir in Patients with Human Immunodeficiency Virus Infection

2006 ◽  
Vol 50 (11) ◽  
pp. 3801-3808 ◽  
Author(s):  
Sara Colombo ◽  
Thierry Buclin ◽  
Matthias Cavassini ◽  
Laurent A. Décosterd ◽  
Amalio Telenti ◽  
...  
Keyword(s):  
Plasma Levels ◽  
Population Analysis ◽  
Pharmacokinetic Profile ◽  
Relative Bioavailability ◽  
Fixed Dose ◽  
Pharmacokinetic Parameters ◽  
Therapeutic Drug ◽  
Population Pharmacokinetic ◽  
Parameter Estimates ◽  
Genetic Traits

ABSTRACT Atazanavir (ATV) is a new azapeptide protease inhibitor recently approved and currently used at a fixed dose of either 300 mg once per day (q.d.) in combination with 100 mg ritonavir (RTV) or 400 mg q.d. without boosting. ATV is highly bound to plasma proteins and extensively metabolized by CYP3A4. Since ATV plasma levels are highly variable and seem to be correlated with both viral response and toxicity, dosage individualization based on plasma concentration monitoring might be indicated. This study aimed to assess the ATV pharmacokinetic profile in a target population of HIV patients, to characterize interpatient and intrapatient variability, and to identify covariates that might influence ATV disposition. A population analysis was performed with NONMEM with 574 plasma samples from a cohort of 214 randomly selected patients receiving ATV. A total of 346 randomly collected ATV plasma levels and 19 full concentration-time profiles at steady state were available. The pharmacokinetic parameter estimates were an oral clearance (CL) of 12.9 liters/h (coefficient of variation [CV], 26%), a volume of distribution of 88.3 liters (CV, 29%), an absorption rate constant of 0.405 h−1 (CV, 122%), and a lag time of 0.88 h. A relative bioavailability value was introduced to account for undercompliance due to infrequent follow-ups (0.81; CV, 45%). Among the covariates tested, only RTV significantly reduced CL by 46%, thereby increasing the ATV elimination half-life from 4.6 h to 8.8 h. The pharmacokinetic parameters of ATV were adequately described by a one-compartment population model. The concomitant use of RTV improved the pharmacokinetic profile. However, the remaining high interpatient variability suggests the possibility of an impact of unmeasured covariates, such as genetic traits or environmental influences. This population pharmacokinetic model, together with therapeutic drug monitoring and Bayesian dosage adaptation, can be helpful in the selection and adaptation of ATV doses.

scholarly journals Dose Tailoring of Vancomycin Through Population Pharmacokinetic Modeling Among Surgical Patients in Pakistan

2021 ◽  
Vol 12 ◽  
Author(s):  
Muhammad Muaaz Munir ◽  
Huma Rasheed ◽  
Muhammad Imran Khokhar ◽  
Rizwan Rasul Khan ◽  
Hafiz Asad Saeed ◽  
...  
Keyword(s):  
Body Weight ◽  
Plasma Concentration ◽  
Goodness Of Fit ◽  
Volume Of Distribution ◽  
Surgical Patients ◽  
Pharmacokinetic Parameters ◽  
Population Pharmacokinetic ◽  
Time Data ◽  
Concentration Data ◽  
Population Pharmacokinetic Modeling

Background: Vancomycin is a narrow therapeutic agent, and it is necessary to optimize the dose to achieve safe therapeutic outcomes. The purpose of this study was to identify the significant covariates for vancomycin clearance and to optimize the dose among surgical patients in Pakistan.Methods: Plasma concentration data of 176 samples collected from 58 surgical patients treated with vancomycin were used in this study. A population pharmacokinetic model was developed on NONMEM® using plasma concentration–time data. The effect of all available covariates was evaluated on the pharmacokinetic parameters of vancomycin by stepwise covariate modeling. The final model was evaluated using bootstrap, goodness-of-fit plots, and visual predictive checks.Results: The pharmacokinetics of vancomycin followed a one-compartment model with first-order elimination. The vancomycin clearance (CL) and volume of distribution (Vd) were 2.45 L/h and 22.6 l, respectively. Vancomycin CL was influenced by creatinine clearance (CRCL) and body weight of the patients; however, no covariate was significant for its effect on the volume of distribution. Dose tailoring was performed by simulating dosage regimens at a steady state based on the CRCL of the patients. The tailored doses were 400, 600, 800, and 1,000 mg for patients with a CRCL of 20, 60, 100, and 140 ml/min, respectively.Conclusion: Vancomycin CL is influenced by CRCL and body weight of the patient. This model can be helpful for the dose tailoring of vancomycin based on renal status in Pakistani patients.

Sign in / Sign up

Export Citation Format

Share Document