scholarly journals Pharmacokinetics and Efficacy of Piperaquine and Chloroquine in Melanesian Children with Uncomplicated Malaria

2007 ◽  
Vol 52 (1) ◽  
pp. 237-243 ◽  
Author(s):  
Harin A. Karunajeewa ◽  
Kenneth F. Ilett ◽  
Ivo Mueller ◽  
Peter Siba ◽  
Irwin Law ◽  
...  
Keyword(s):  
Half Life ◽  
Uncomplicated Malaria ◽  
Active Metabolite ◽  
High Performance ◽  
Compartment Model ◽  
Volume Of Distribution ◽  
Two Compartment Model ◽  
Elimination Half ◽  
Median Volume ◽  
Intensive Sampling

ABSTRACT The disposition of chloroquine (CQ) and the related 4-aminoquinoline, piperaquine (PQ), were compared in Papua New Guinean children with uncomplicated malaria. Twenty-two children were randomized to 3 days of PQ phosphate at 20 mg/kg/day (12 mg of PQ base/kg/day) coformulated with dihydroartemisinin (DHA-PQ), and twenty children were randomized to 3 days of CQ at 10 mg base/kg/day with a single dose of sulfadoxine-pyrimethamine (CQ-SP). After a 42-day intensive sampling protocol, PQ, CQ, and its active metabolite monodesethyl-chloroquine (DECQ) were assayed in plasma by using high-performance liquid chromatography. A two-compartment model with first-order absorption was fitted to the PQ and CQ data. There were no significant differences in age, gender, body weight, or admission parasitemia between the two groups. The PCR-corrected 42-day adequate clinical and parasitological responses were 100% for DHA-PQ and 94% for CQ-SP, but P. falciparum reinfections during follow-up were common (33 and 18%, respectively). For PQ, the median volume of distribution at steady state, allowing for bioavailability (V ss/F), was 431 liters/kg (interquartile range [IQR], 283 to 588 liters/kg), the median clearance (CL/F) was 0.85 liters/h/kg (IQR, 0.67 to 1.06 liters/h/kg), the median distribution half-life (t 1/2 α) was 0.12 h (IQR, 0.05 to 0.66 h), and the median elimination half-life (t 1/2 β) was 413 h (IQR, 318 to 516 h). For CQ, the median V ss/F was 154 liters/kg (IQR, 101 to 210 liters/kg), the median CL/F was 0.80 liters/h/kg (IQR, 0.52 to 0.96 liters/h/kg), the median t 1/2 α was 0.43 h (IQR, 0.05 to 1.82 h), and the median t 1/2 β was 233 h (IQR, 206 to 298 h). The noncompartmentally derived median DECQ t 1/2 β was 290 h (IQR, 236 to 368 h). Combined molar concentrations of DECQ and CQ were higher than those of PQ during the elimination phase. Although PQ has a longer t 1/2 β than CQ, its prompt distribution and lack of active metabolite may limit its posttreatment malaria-suppressive properties.

scholarly journals Effect of Concomitant Artesunate Administration and Cytochrome P4502C8 Polymorphisms on the Pharmacokinetics of Amodiaquine in Ghanaian Children with Uncomplicated Malaria

2008 ◽  
Vol 52 (12) ◽  
pp. 4400-4406 ◽  
Author(s):  
George O. Adjei ◽  
Kim Kristensen ◽  
Bamenla Q. Goka ◽  
Lotte C. G. Hoegberg ◽  
Michael Alifrangis ◽  
...  
Keyword(s):  
Body Weight ◽  
Uncomplicated Malaria ◽  
Population Distribution ◽  
Parasite Clearance ◽  
Compartment Model ◽  
Volume Of Distribution ◽  
Maximum Plasma ◽  
Two Compartment Model ◽  
Elimination Half ◽  
Wide Variability

ABSTRACT Artesunate (AS) is used in combination with amodiaquine (AQ) as first-line treatment for uncomplicated malaria in many countries. We investigated the effect of concomitant AS administration on the pharmacokinetics of AQ and compared concentrations of desethylamodiaquine (DEAQ), the main metabolite of AQ, in plasma between patients with different variants of the cytochrome P4502C8 (CYP2C8) gene. A two-compartment model was fitted to 169 plasma DEAQ concentrations from 103 Ghanaian children aged 1 to 14 years with uncomplicated malaria treated either with AQ alone (n = 15) or with AS plus AQ (n = 88). The population clearance of DEAQ appeared to increase nonlinearly with body weight, and the central volume of distribution of DEAQ was higher (P < 0.001) in the AS-plus-AQ group than in the AQ-only group. The maximum plasma DEAQ concentration was higher (P < 0.001), and the population distribution half-life was shorter (P < 0.01), in the AQ-only group than in the AS-plus-AQ group. The total areas under the plasma DEAQ concentration-time curves (P = 0.68) and elimination half-lives (P = 0.39) were similar for the two groups. There was a high frequency (0.179) of the non-wild-type allele of CYP2C8, but no differences between CYP2C8 genotypes with regard to AQ efficacy or safety were evident. The sample size, however, was limited, so monitoring of AQ toxicity in the study area is still indicated. The nonlinear clearance of DEAQ and the wide variability in kinetic parameters have safety implications for weight-based dosing of higher-body-weight children with AQ. The pharmacokinetics of artemisinin combination therapies should be studied in malaria patients, because the rapid parasite clearance caused by the artemisinin may affect the kinetics of the partner drug and the combination.

Steady-State Pharmacokinetics of Cefoperazone and Sulbactam in Patients with Acute Appendicitis

1994 ◽  
Vol 28 (6) ◽  
pp. 703-707
Author(s):  
Larry H. Danziger ◽  
Stephen C. Piscitelli ◽  
Donna J. Occhipinti ◽  
Daniel J. Resnick ◽  
Keith A. Rodvold
Keyword(s):  
Steady State ◽  
Acute Appendicitis ◽  
Dosage Reduction ◽  
Area Under The Curve ◽  
Compartment Model ◽  
Hepatic Function ◽  
Volume Of Distribution ◽  
Two Compartment Model ◽  
Elimination Half ◽  
G Prior

OBJECTIVE: To determine the steady-state pharmacokinetics of intravenously administered cefoperazone and sulbactam when given in combination to patients with acute appendicitis. METHODS: Six patients with normal renal and hepatic function received cefoperazone 2 g with sulbactam 1 g prior to appendectomy and then every 12 hours. Serial blood samples were collected after each patient received at least three doses of cefoperazone/sulbactam. RESULTS: Cefoperazone and sulbactam could be best described by a two-compartment model. Mean ± SD values for cefoperazone steady-state volume of distribution (Vssd), elimination half-life (t1/2β), clearance (Cl), and area under the curve (AUC0-t) were 19.8 ± 8.0 L, 3.97 ± 1.06 h, 62.6 ± 16.3 mL/min, and 556.9 ± 122.0 mg·h/L, respectively. Sulbactam Vssd, t1/2β, Cl, and AUC0-t were 34.7 ± 13.9 L, 1.39 ± 0.4 h, 288.6 ± 68.2 mL/min, and 64.8 ± 24.5 mg·h/L, respectively. CONCLUSIONS: Compared with data from healthy volunteers, cefoperazone exhibited a decreased Cl and increased Vssd and t1/2β in patients with acute appendicitis. An increased Vssd also was observed for sulbactam. The disposition of cefoperazone/sulbactam is altered in this group of patients; however, these changes are not likely to warrant a dosage reduction.

Doxorubicin clearance in the obese.

1988 ◽  
Vol 6 (8) ◽  
pp. 1321-1327 ◽  
Author(s):  
K A Rodvold ◽  
D A Rushing ◽  
D A Tewksbury
Keyword(s):  
Body Weight ◽  
Half Life ◽  
High Performance ◽  
Area Under The Curve ◽  
Ideal Body Weight ◽  
Apparent Volume ◽  
Volume Of Distribution ◽  
Obese Patients ◽  
Elimination Half Life ◽  
Elimination Half

A study was carried out to examine the effect, if any, of obesity on doxorubicin pharmacokinetics. Body weight was found to be significantly related to doxorubicin clearance (r = -.75; P less than .001) and elimination half-life (r = .62; P = .003). Thus, the contribution of obesity on pharmacokinetics of antineoplastic agents should be taken into consideration in the analysis of clinical data with respect to toxicity and tumor response. Twenty-one patients were studied with their first course of doxorubicin (50 to 70 mg/m2) administered as a 60-minute intravenous (IV) infusion. Patients were divided into three groups on the basis of percentage of ideal body weight (IBW): normal (less than 115% IBW), mildly obese (115% to 130% IBW), and obese (greater than 130% IBW). Blood samples were collected up to 48 hours after the infusion and analyzed for doxorubicin and its metabolite, doxorubicinol, by high performance liquid chromatography. Doxorubicin area under the curve (AUC) was greater in obese than in normal patients (2,209 v 1,190 ng h/mL; P less than .05), yielding correspondingly reduced systemic clearance of the agent in obese patients (891 v 1,569 mL/min; P less than .001). The mean elimination half-life (T1/2) was 20.4 hours in the obese patients and 13.0 hours in the normal patients. The apparent volume of distribution (Vss) was not significantly different among the three groups of patients, indicating that the prolonged T1/2 in the obese patients is due to the reduction in clearance. The AUC and T1/2 of doxorubicinol were similar among all patient groups.

scholarly journals Herb-Drug Pharmacokinetic Interaction of a Traditional Chinese Medicine Jia-Wei-Xiao-Yao-San with 5-Fluorouracil in the Blood and Brain of Rat Using Microdialysis

2015 ◽  
Vol 2015 ◽  
pp. 1-11 ◽  
Author(s):  
Meng-Hsuan Chiang ◽  
Li-Wen Chang ◽  
Ju-Wen Wang ◽  
Lie-Chwen Lin ◽  
Tung-Hu Tsai
Keyword(s):  
Chinese Medicine ◽  
Half Life ◽  
High Performance ◽  
Pharmacokinetic Interaction ◽  
Volume Of Distribution ◽  
Research Database ◽  
Elimination Half Life ◽  
Elimination Half ◽  
Drug Pharmacokinetic ◽  
The Brain

According to a survey from the National Health Insurance Research Database (NHIRD), Jia-Wei-Xiao-Yao-San (JWXYS) is the most popular Chinese medicine for cancer patients in Taiwan. 5-Fluorouracil (5-FU) is a general anticancer drug for the chemotherapy. To investigate the herb-drug interaction of JWXYS on pharmacokinetics of 5-FU, a microdialysis technique coupled with a high-performance liquid chromatography system was used to monitor 5-FU in rat blood and brain. Rats were divided into four parallel groups, one of which was treated with 5-FU (100 mg/kg, i.v.) alone and the remaining three groups were pretreated with a different dose of JWXYS (600, 1200, or 2400 mg/kg/day for 5 consecutive days) followed by a combination with 5-FU. This study demonstrates that 5-FU with JWXYS (600 mg/kg/day or 1200 mg/kg/day) has no significant effect on the pharmacokinetics of 5-FU in the blood and brain. However, JWXYS (2400 mg/kg/day) coadministered with 5-FU extends the elimination half-life and increases the volume of distribution of 5-FU in the blood. The elimination half-life of 5-FU in the brain for the pretreatment group with 2400 mg/kg/day of JWXYS is significantly longer than that for the group treated with 5-FU alone and also reduces the clearance. This study provides practical dosage information for clinical practice and proves the safety of 5-FU coadministered with JWXYS.

Trastuzumab (T) and everolimus (E) pharmacokinetics (PK) in HER2 positive (+) primary breast cancer (BC) patients (pts): Unicancer RADHER trial results.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 2599-2599
Author(s):  
Guillemette Bernadou ◽  
Keyvan Rezai ◽  
Jean-Louis Merlin ◽  
Mario Campone ◽  
Francois Lokiec ◽  
...  
Keyword(s):  
Body Weight ◽  
Half Life ◽  
Tumor Volume ◽  
Compartment Model ◽  
Her2 Positive ◽  
Elimination Half Life ◽  
A Value ◽  
Two Compartment Model ◽  
Elimination Half ◽  
The Impact

2599 Background: T has greatly modified the prognosis of HER2+ BC, but few studies have analyzed its PK. The RADHER study evaluated the interest of adding E to T as preoperative therapy for primary HER2+ BC. It also aimed at describing the PK of T and studying the impact of E with T in primary BC. Methods: Eligible pts with HER2+ operable primary BC were randomized to receive T alone (loading dose 4 mg/kg, then 2 mg/kg/week (W)) or T + E (10 mg/day (D)) for a 6-W pre-operative treatment. Blood samples were collected to measure T and E concentrations. For T, plasma samples were collected in all pts before each infusion, and at Hour (H) 1, D1, D3, W1, W2, W4, W8 and W12 after the last infusion. E concentrations were determined on whole blood collected at H0, H0.5, H1, H2, H4, H6, H12 and H24 after the first T infusion, and again after the last E intake. T and E PK were described using population compartment analyses. Results: From 82 pts randomized, 79 were evaluable for T and 22 for E PK. Mean estimated PK parameters of T were (interindividual coefficient of variation %): central (Vc) and peripheral (Vp) volumes of distribution = 2 L (24%) and 1.3 L (39%), systemic (CL) and intercompartment (Q) clearances = 0.22 L/day (19%) and 0.36 L/day, respectively. Vc increased with body weight and decreased with age, while CL increased with body weight and with tumor volume. Elimination half-life was 11 days, a value lower than that previously reported in metastatic BC (28 days). E PK was best described by a two-compartment model. Mean estimated PK parameters (RSE%) of E were: CL = 3.96 L/h (22%), Q = 29.1 L/h (7%), Vc = 119 L (11%), Vp = 1530 L (24%). E did not influence T PK. E PK was similar to that previously reported in other indications. Conclusions: This is the first study describing the PK of T and E in primary BC. Notably, T CL increases with tumor volume and the elimination half-life is only 11 days, lower than expected from previous results in metastatic BC. The differences in PK between primary and metastatic BC might lead to take a second look at trastuzumab dose regimen in primary BC. Clinical trial information: NCT00674414.

scholarly journals Erythropoietin kinetics in rats: generation and clearance

Blood ◽  
1986 ◽  
Vol 67 (3) ◽  
pp. 646-649 ◽  
Author(s):  
SE Steinberg ◽  
JF Garcia ◽  
GR Matzke ◽  
J Mladenovic
Keyword(s):  
Intravenous Injection ◽  
Plasma Volume ◽  
Rat Model ◽  
Clearance Rate ◽  
Half Life ◽  
Plasma Clearance ◽  
Compartment Model ◽  
Volume Of Distribution ◽  
Two Compartment Model ◽  
Disappearance Curve

Abstract Detailed studies to analyze the early events of erythropoietin (Ep) secretion and clearance were performed in a rat model using a double antibody radioimmunoassay. Ep clearance was determined following intravenous injection of 1 mL of Ep-rich plasma, 1,080 mU/mL, obtained from phlebotomized rats. Analysis revealed a disappearance curve that conformed to a two-compartment model with an alpha half-life t1/2 of 3.6 minutes and a beta t1/2 of 86 minutes. The volume of distribution was similar to the calculated plasma volume. In anephric animals, there was no change in the plasma clearance rate or the volume of distribution. Rapid Ep secretion was elicited by a single 15 mL/kg phlebotomy (hematocrit decrement 45% to 30%), so that levels reached 20 to 30 times baseline (524 +/- 76 v 24 +/- 7 mU/mL) at five hours, whereas they plateaued for at least 33 hours. The increase in the rate of secretion was geometric, from 9.9 mU/h baseline secretion to 429 mU/h. These data identify a very sensitive and rapidly responsive system for Ep modulation in the rat.

scholarly journals Influences of tolfenamic acid and flunixin meglumine on the disposition kinetics of levofloxacin in sheep

2020 ◽  
Vol 68 (1) ◽  
pp. 65-70 ◽  
Author(s):  
Duygu Durna Corum ◽  
Orhan Corum ◽  
Ramazan Yildiz ◽  
Hatice Eser Faki ◽  
Merve Ider ◽  
...  
Keyword(s):  
Half Life ◽  
High Performance ◽  
Plasma Concentrations ◽  
Volume Of Distribution ◽  
Tolfenamic Acid ◽  
Time Curve ◽  
Inflammatory Conditions ◽  
Flunixin Meglumine ◽  
Model Following ◽  
Elimination Half

AbstractThe pharmacokinetics of levofloxacin (4 mg/kg), administered both alone and in combination with tolfenamic acid (2 mg/kg) and flunixin meglumine (2.2 mg/kg), was established after intravenous administration in sheep. Plasma levofloxacin concentrations were assayed by high-performance liquid chromatography and analysed according to the two-compartment open model. Following the administration of levofloxacin alone, the mean distribution half-life, elimination half-life, total clearance, volume of distribution at steady state and area under the plasma concentration–time curve were 0.20 h, 1.82 h, 0.39 L/h/kg, 0.96 L/kg and 10.40 h × µg/mL, respectively. Tolfenamic acid and flunixin meglumine caused a slow elimination and increased plasma concentrations of levofloxacin in combination administration. Levofloxacin, with an alteration in the dosage regimen, can be used effectively with tolfenamic acid and flunixin meglumine for the therapy of infections and inflammatory conditions in sheep.

Pharmacokinetic studies on Sulfamonomethoxine in rabbits

2019 ◽  
Vol 20 (2) ◽  
pp. 92-97
Author(s):  
M Amer ◽  
M Elsayed ◽  
S Kazawaki ◽  
W Fathy ◽  
Eman El-Ashry
Keyword(s):  
Half Life ◽  
Area Under The Curve ◽  
Compartment Model ◽  
Volume Of Distribution ◽  
The Body ◽  
Pharmacokinetic Studies ◽  
Plasma Drug ◽  
Time Data ◽  
Drug Concentrations ◽  
Two Compartment Model

The present study was performed to determine the pharmacokinetics of sulfamonomethoxine (20mg/kg) in 5 rabbits after its oral and intravenous administration. Blood samples were collected immediately before (time 0) and at 0.08, 0.25, 0.5, 1, 3, 5 and 8 hours post-dosing to evaluate the pharmacokinetics of sulfamonomethoxine. Plasma sulfamonomethoxine concentrations were quantified with HPLC-UV, and plasma drug concentration versus time data after IV was best fitted to the two-compartment model, characterized with the distribution phase (α) equaled to 2.05 h-1 with a distribution half-life [t0.5(α)] equaled to 0.61 h. The volume of distribution of (V1c) was 0.15 ml/kg., whereas the volume of distribution at a steady – state [Vdss] was 0.20 ml/kg, and the body clearance was 0.03 ml/ kg / h. After oral administration of SMM, plasma drug concentrations were best fitted to a two-compartment model, of which the mean half-life of absorption (t1/2ab) and elimination (t1/2β) were 0.02 and 1.99 h, respectively. The maximal absorption concentration (Cmax) was estimated as 114.06 µg/ml at 0.12 h, and the Area under the curve (AUC) was 340.42 µg/ml/h.

Pharmacokinetics of MMB4 DMS in Rats, Rabbits, and Dogs Following a Single IV Administration

2013 ◽  
Vol 32 (4_suppl) ◽  
pp. 30S-37S ◽  
Author(s):  
S. Peter Hong ◽  
Seth T. Gibbs ◽  
Dean J. Kobs ◽  
Merrill R. Osheroff ◽  
Jerry D. Johnson ◽  
...  
Keyword(s):  
Half Life ◽  
Systemic Exposure ◽  
Compartment Model ◽  
Central Compartment ◽  
Volume Of Distribution ◽  
Sprague Dawley ◽  
Elimination Half Life ◽  
Sprague Dawley Rats ◽  
Elimination Half ◽  
Op Nerve Agents

Organophosphorus (OP) nerve agents pose tremendous threats to both military and civilian populations. The substance 1,1′-methylenebis[4-[(hydroxyimino)methyl]-pyridinium] (MMB4) is being developed as a replacement for the currently fielded 2-pyridine aldoxime, or pralidoxime (2-PAM) as a treatment for OP nerve agent–induced toxicity. The present study characterized pharmacokinetic (PK) profiles of MMB4 in male and female Sprague-Dawley rats, New Zealand White rabbits, and beagle dogs given a single intravenous (IV) administration of MMB4 dimethanesulfonate (DMS) at 55, 25, and 15 mg/kg dose, respectively. The plasma MMB4 concentration versus time profiles were biphasic for all species tested and fit a 2-compartment model with first-order elimination. There were no overt sex-related differences in the calculated PK parameters. For the rat, rabbit, and dog, the average systemic exposure parameters predicted Cmax (µg/mL) and AUC∞ (µg·h/mL) were 273 and 71.0, 115 and 48.1, and 87.4 and 39.6; the average volume of distribution (mL/kg) values to the central and peripheral compartments were 207 and 143, 242 and 172, and 198 and 213; and the average elimination half-life (hour) and clearance (mL/h/kg) values were 0.18 and 778, 0.29 and 577, and 0.32 and 430, respectively, when the PK parameters for males and females were combined. The current study revealed a similarity in the volume of distribution to the central compartment for MMB4 among the 3 species tested while demonstrating species-related differences in the elimination half-life and clearance of MMB4.

Biodistribution, plasma kinetics and quantification of single-pass pulmonary clearance of adrenomedullin

2005 ◽  
Vol 109 (1) ◽  
pp. 97-102 ◽  
Author(s):  
Jocelyn DUPUIS ◽  
Alexandre CARON ◽  
Nathalie RUËL
Keyword(s):  
Half Life ◽  
Compartment Model ◽  
Single Pass ◽  
Pulmonary Clearance ◽  
Two Compartment Model ◽  
Elimination Half ◽  
Calcitonin Gene ◽  
First Pass ◽  
Specific Receptors

The biodistribution, pharmacokinetics and multi-organ clearance of the vasodilator peptide AM (adrenomedullin) were evaluated in rats and its single-pass pulmonary clearance was measured in dogs by the indicator-dilution technique. Intravenously administered 125I-rAM(1–50) [rat AM(1–50)] was rapidly cleared following a two-compartment model with a very rapid distribution half-life of 2.0 min [95% CI (confidence interval), 1.98–2.01] and an elimination half-life of 15.9 min (95% CI, 15.0–16.9). The lungs retained most of the injected activity with evidence of single-pass clearance, since retention was lower after intra-arterial (13.5±0.6%) compared with intravenous (30.4±1.5%; P<0.001) injection. Lung tissue levels of total endogenous AM were 20-fold higher than in other organs with no difference in plasma levels across the pulmonary circulation. In dogs, there was 36.4±2.1% first-pass unidirectional extraction of 125I-rAM(1–50) by the lungs that was reduced to 21.9±2.4% after the administration of unlabelled rAM(1–50) (P<0.01). Extraction was not affected by calcitonin-gene-related peptide administration (40.6±2.9%), but was slightly reduced by the C-terminal fragment of human AM(22–52) (31.4±3.3%; P<0.01). These data demonstrate that the lungs are a primary site for AM clearance in vivo with approx. 36% first-pass extraction through specific receptors. This suggests that the lungs not only modulate circulating levels of this peptide, but also represent its primary target.

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