Pharmacokinetics of single-dose rivaroxaban under fed state in obese vs. non-obese subjects: An open-label controlled clinical trial (RIVOBESE-PK).

The evidence of rivaroxaban's pharmacokinetics in obese compared with non-obese populations remains inconclusive. We aimed to compare the pharmacokinetic profile of rivaroxaban between obese and non-obese populations under fed state. Participants who met the study's eligibility criteria were assigned into one of two groups: obese (body mass index ≥35 kg/m2) or non-obese (body mass index 18.5-24.9 kg/m2). A single dose of rivaroxaban 20 mg was orally administered to each participant. Nine blood samples over 48 h, and multiple urine samples over 18 h were collected and analyzed for rivaroxaban concentration using ultra-performance liquid chromatography coupled with tandem mass detector. Pharmacokinetic parameters were determined using WinNonlin software. Thirty-six participants were recruited into the study. No significant changes were observed between obese and non-obese participants in peak plasma concentration, time to reach peak plasma concentration, area under the plasma concentration-time curve over 48 h or to infinity, elimination rate constant, half-life, apparent volume of distribution, apparent clearance, and fraction of drug excreted unchanged in urine over 18 h. Rivaroxaban's exposure was similar between the obese and non-obese subjects, and there were no significant differences in other pharmacokinetic parameters between the two groups. These results suggest that dose adjustment for rivaroxaban is probably unwarranted in the obese population.

Impact of valproic acid on busulfan pharmacokinetics: In vitro assessment of potential drug-drug interaction.

Busulfan (Bu) is an alkylating agent commonly used at high doses in the preparative regimens of hematopoietic stem cell transplantation (HSCT). It has been shown that such high doses of Bu are associated with generalized seizures which are usually managed by prophylactic antiepileptic drugs (AEDs) such as valproic acid (VPA). Being a strong enzyme inhibitor, VPA may inhibit Bu metabolism and thus increase its potential toxicity. Despite its clinical relevance, the potential interaction between Bu and VPA has not yet been evaluated. The aim of the present study was to assess and evaluate the potential drug-drug interaction (DDI) between Bu and VPA. This study was carried out by incubating Bu in laboratory-prepared rat liver-subcellular fractions including S9, microsomes, and cytosol, alone or in combination with VPA. The liver fractions were prepared by differential centrifugation of the liver homogenate. Analysis of Bu was employed using a fully validated LC-MS/MS method. The validation parameters were within the proposed limits of the international standards guidelines. Bu metabolic stability was assessed by incubating Bu at a concentration of 8 µg/ml in liver fractions at 37°C. There were significant reductions in Bu levels in S9 and cytosolic fractions, whereas these levels were not significantly (P ˃ 0.05) changed in microsomes. However, in presence of VPA, Bu levels in S9 fraction remained unchanged. These results indicated, for the first time, the potential metabolic interaction of Bu and VPA being in S9 only. This could be explained by inhibiting Bu cytosolic metabolism by the interaction with VPA either by sharing the same metabolic enzyme or the required co-factor. In conclusion, the present findings suggest, for the first time, a potential DDI between Bu and VPA in vitro using rat liver fractions. Further investigations are warranted in human-derived liver fractions to confirm such an interaction.

UPLC-Tandem Mass Spectrometry for Quantification of Busulfan in Human Plasma: Application to Therapeutic Drug Monitoring.

Busulfan (Bu) is an alkylating agent commonly used in preparative regimens for hematologic malignant and non-malignant patients undergoing hematopoietic stem cell transplantation (HSCT). The objective of the present study was to develop an UPLC-MS/MS method for quantification of Bu in human plasma. A total of 55 patients with hematologic malignancies (n = 34) and non- malignancies (n = 21) received myeloablative Bu therapy prior to HSCT. A tandem mass spectrometric method was developed and validated to quantify Bu levels in these patients. The method was fully validated over the concentration range of 25-2000 ng/mL (r > 0.99). The assay method demonstrated good precision and accuracy. Stability studies indicated that the drug was stable in various conditions. Incurred sample reanalysis findings were within acceptable ranges (<15% of the nominal concentration). Based on the 1st dose AUC results, one third of hematologic malignant patients and half of non-malignant patients needed dose adjustment. However, in subsequent doses (5th, 9th, and 13th), 77%, 82% and 82%, respectively, of hematologic malignant patients and 71%, 67% and 86%, respectively, of non-malignant patients achieved the target range of Bu AUC. The suitability of the developed method for routine TDM of Bu in HSCT patients was demonstrated. The study suggests that the pharmacokinetic profile of Bu varies in both groups.

Quantification of Colistin in Plasma by Liquid Chromatography-Tandem Mass Spectrometry: Application to a Pharmacokinetic Study.

Colistin is a polymixin antibiotic (polymixin E) that is produced by Bacillus colistinus bacteria. The aim of the present study was to develop and validate a method to quantify colistin levels in plasma using high performance liquid chromatography-tandem mass spectrometry (LC-MS/MS) technique and then apply it in experimental animals (rats) to investigate the pharmacokinetic profile of colistin in this species. Polymyxin B was used as an internal standard (IS) and the quantitation was carried out using ESI + interface and employing multiple reaction monitoring (MRM) mode. A mobile phase consisting of acetonitrile:water:formic acid (30:70:0.1%; v/v/v) was employed and Zorbax eclipse plus C18 (1.8 µm, 2.1 mm i.d. x 50 mm) was the optimal column for this method and utilized at a flow rate of 0.2 mL/min. The full scan mass spectra of precursor/product ions of colistin A were at m/z 585.5 > 100.8, for colistin B at m/z 578.8 > 101 and for the IS at m/z 602.8 > 101. The lower limit of quantification (LLOQ) was 0.5 µg/mL. The method demonstrated acceptable intra-run and inter-run precision and accuracy for both colistin A and colistin B. Colistin was stable when assessed for long-term stability, freeze-thaw stability and autosampler stability. However, it was not stable when stored at room temperature. The matrix effect evaluation showed minimal or no effect. Incurred sample reanalysis findings were within acceptable ranges (<20% of the nominal concentration). The pharmacokinetic parameters of colistin were investigated in rats using the present method. The developed method for colistin demonstrates that it is rapid, sensitive, specific, accurate, precise, and reliable.

Effect of experimentally induced hepatic and renal failure on the pharmacokinetics of topiramate in rats.

We aimed to investigate the effect of induced hepatic and renal failure on the pharmacokinetics of topiramate (TPM) in rats. Twenty-four Sprague-Dawley rats were used in this study. Renal or hepatic failure was induced by a single i.p. dose of 7.5 mg/kg cisplatin (n = 8) or 0.5 mL/kg carbon tetrachloride (CCl4) (n = 8), respectively. Three days after cisplatin dose or 24 h after CCl4 dose, the rats were administered a single oral dose of 20 mg/kg TPM. The plasma samples were quantified by LC-MS/MS method. Compared to control, plasma concentration-time profile in CCl4-treated and, to a lesser extent, in cisplatin-treated rats decreased more slowly particularly in the elimination phase. TPM oral clearance (CL/F) in CCl4-treated group was significantly lower than that in control (P < 0.001), whereas AUC0-∞, T1/2, and Vd/F were significantly higher in CCl4-treated rats compared to the control (P < 0.01). The CL/F was not significantly different between cisplatin-treated rats and control (P > 0.05). However, in cisplatin-treated rats, the T1/2 and Vd/F were significantly higher than that in the control group (P < 0.01). Both conditions failed to cause a significant effect on Cmax or Tmax. The present findings suggest that induced hepatic or renal failure could modify the pharmacokinetic profile of TPM in the rat.

A simple and accurate liquid chromatography-tandem mass spectrometry method for quantification of zonisamide in plasma and its application to a pharmacokinetic study.

Zonisamide (ZNM) is an antiepileptic drug that is used as an adjunctive therapy in the treatment of adults with partial seizures. An LC-MS/MS method for quantification of ZNM in human and rabbit plasma using (2)H4,(15)N-Zonisamide as an internal standard (IS) has been developed and validated. The drug and IS were extracted by ether and analyzed on Symmetry(®) C18 column. Quantitation was achieved using ESI-interface employing MRM mode. The method was validated over the concentration range of 0.5-50µg/mL and 0.5-30µg/mL (r(2)>0.99) in human and rabbit plasma samples, respectively. Intra- and inter-run precision of ZNM assay in human and rabbit plasma samples ranged from 0.8 to 8.5% with accuracy (bias) varied from -11.3 to 14.4% indicating good precision and accuracy. Stability of ZNM in human and rabbit plasma samples at various conditions showed that the drug was stable under the studied conditions. Analytical recoveries of ZNM and IS from spiked human and rabbit plasma samples were in the range of 70.8-77.3% and 85.6-110.4%, respectively. Matrix effect study showed a lack of matrix effect on mass ions of ZNM and IS. The developed method was successfully applied for a pharmacokinetic study by measuring ZNM in rabbit plasma samples. Moreover, the method is routinely utilized for TDM of ZNM.

Pharmacokinetics of artesunate alone and in combination with sulfadoxine/pyrimethamine in healthy Sudanese volunteers.

Artesunate (AS) in combination with sulfadoxine/pyrimethamine (SP) is the first-line therapy for management of uncomplicated Plasmodium falciparum malaria in Sudan. The objective of this study was to assess the potential impact of SP on the pharmacokinetics of AS and its active metabolite, dihydroartemisinin (DHA), in healthy adults. A single-dose, randomized, open-label, crossover study design with a washout period of three weeks was performed with 16 volunteers. After oral administration of AS alone or in combination with SP, Tmax values of AS and DHA were significantly prolonged in the combination group (P < 0.05). However, there was no significant effect on the other pharmacokinetic parameters (P > 0.05). The t1/2 values of AS and DHA were significantly higher in females than in males (P < 0.05). The present findings suggest that co-administration of SP with AS has no clinically relevant impact on the pharmacokinetics of AS or DHA in healthy persons.

Amikacin population pharmacokinetics in critically ill Kuwaiti patients.

Amikacin pharmacokinetic data in Kuwaiti (Arab) intensive care unit (ICU) patients are lacking. Fairly sparse serum amikacin peak and trough concentrations data were obtained from adult Kuwaiti ICU patients. The data were analysed using a nonparametric adaptive grid (NPAG) maximum likelihood algorithm. The estimations of the developed model were assessed using mean error (ME) as a measure of bias and mean squared error (MSE) as a measure of precision. A total of 331 serum amikacin concentrations were obtained from 56 patients. The mean (± SD) model parameter values found were Vc = 0.2302 ± 0.0866 L/kg, kslope = 0.004045 ± 0.00705 min per unit of creatinine clearance, k12 = 2.2121 ± 5.506 h(-1), and k21 = 1.431 ± 2.796 h(-1). The serum concentration data were estimated with little bias (ME = -0.88) and good precision (MSE = 13.08). The present study suggests that amikacin pharmacokinetics in adult Kuwaiti ICU patients are generally rather similar to those found in other patients. This population model would provide useful guidance in developing initial amikacin dosage regimens for such patients, especially using multiple model (MM) dosage design, followed by appropriate Bayesian adaptive control, to optimize amikacin dosage regimens for each individual patient.

Impact of pregnancy on zonisamide pharmacokinetics in rabbits.

Pregnancy is associated with various physiological changes which may lead to significant alterations in the pharmacokinetics of many drugs. The present study was aimed to investigate the potential effects of pregnancy on the pharmacokinetic profile of zonisamide (ZNM) in the rabbit. Seven female rabbits were used in this study. The pregnant and nonpregnant rabbits received ZNM orally at a dose of 10 mg/kg and blood samples were collected from the animals just before receiving the drug and then serially for up to 24 h. The plasma samples were analyzed using tandem mass spectrometric method. Following a single oral dose of ZNM to the rabbits, the mean values of ZNM plasma concentrations at different times were consistently low in pregnant compared to nonpregnant rabbits. The mean values of ZNM's Cmax and AUC0-∞ were significantly (P < 0.05) decreased, whereas the CL/F exhibited substantial increase (P < 0.05) in pregnant compared to nonpregnant rabbits. Tmax, t1/2abs, t1/2el, MRT, and Vd/F showed no significant differences between the two groups. The present study demonstrates that pregnancy decreased ZNM plasma concentrations in rabbits and that the decrease could be due to decreased extent of gastrointestinal absorption, induced hepatic metabolism, or enhanced renal elimination of the drug.

Effect of pregnancy on topiramate pharmacokinetics in rabbits.

Pregnancy is associated with various physiological changes that may lead to significant alterations in the pharmacokinetic profiles of many drugs. The present study was designed to investigate the potential effects of pregnancy on the pharmacokinetics of topiramate (TPM) in the rabbit model. Nineteen female New Zealand white rabbits (nine pregnant and 10 non-pregnant) were used in this study. Blood samples were collected from the animals just before receiving TPM orally at a dose of 20 mg/kg and then serially for up to 24 h. TPM plasma samples were analysed using a validated tandem mass spectrometric (LC-MS/MS) method. The mean values of TPM pharmacokinetic parameters (t(1/2), T(max), AUC(0-∞), and CL/F) were significantly modified in pregnant rabbits as compared with non-pregnant group. Pregnancy significantly (P < 0.05) increased TPM half-life (t(1/2)), time to attain the maximum plasma concentration (T(max)), and the area under TPM plasma concentration-time curve (AUC(0-∞)) and decreased the drug's oral clearance (CL/F) compared with non-pregnancy state in rabbits. The present study demonstrates that pregnancy alters the pharmacokinetics of TPM in rabbits in late gestational period and considerable inter-animal variability was observed. The findings of the present study indicate that TPM CL/F is decreased during late pregnancy in the rabbit model.

Liquid chromatography-tandem mass spectrometric method for determination of E121 in mouse plasma and its application to pharmacokinetics.

A rapid LC-MS/MS method for quantification of an enaminone analog, E121 in mouse plasma using E118 as an internal standard (IS) has been developed and validated. The analyte was analyzed on C(18) column using a mobile phase of acetonitrile/methanol/ammonium acetate/formic acid (60:20:20:0.025, v/v/v/v) at a flow rate of 0.25 mL/min. Quantitation was achieved using ESI+ interface, employing MRM mode at m/z 308>262 and 222>194 for E121 and IS, respectively. The calibration standards were linear over a range of 0.10-20 microg/mL (r(2)>0.99) with an LLOQ of 0.1 microg/mL (RSD%; 11.4% and bias%; 9.5%). Intra- and inter-run precision of E121 assay ranged from 3.7 to 10.9% with accuracy (bias) that varied between -10.0 and 12.0%, demonstrating good precision and accuracy. Recoveries of E121 and the IS from plasma were above 80%. Stability of E121 in plasma showed that the analyte was stable under various conditions. The matrix effect study showed a lack of effect. The applicability of the developed method was demonstrated by measuring E121 in mouse plasma samples following intraperitoneal administration of various doses ranging from 10 to 100 mg/kg and this study demonstrates that E121 exhibits linear kinetics in the dose range studied.

Therapeutic drug monitoring of topiramate by liquid chromatography-tandem mass spectrometry.

BACKGROUND: Topiramate (TPM) is a new antiepileptic drug (AED) used worldwide in patients with various types of epilepsies and also for prophylaxis of migraine. A rapid, selective, reliable, precise, accurate, and reproducible tandem mass spectrometric (MS/MS) method for quantification of TPM in human plasma using topiramate-d12 as an internal standard (IS) has been developed and validated to be used routinely for TDM of TPM. METHODS: The drug and IS were extracted by ether and analyzed on Symmetry C18 column. Quantitation was achieved using ESI-interface employing MRM mode. RESULTS: The method was validated over the concentration range of 0.5-30 microg/ml (r>0.99). Intra- and inter-run precisions of TPM assay at three concentrations ranged from 0.7 to 7.8% with accuracy (bias) varied from -10.0 to 2.1% indicating good precision and accuracy. Analytical recoveries of TPM and IS from spiked human plasma were in the range of 84.1 to 90.0% and 90.0 to 111.0%, respectively. Stability of TPM in human plasma samples at different conditions showed that the drug was stable under the studied conditions. Matrix effect study showed a lack of matrix effect on mass ions of TPM and IS. CONCLUSION: The described method compared well when assessed by Heathcontrol TDM theme program (r>0.99). The suitability of the developed method for TDM was demonstrated by measuring TPM in human plasma samples of epileptic patients treated with TPM. The proposed method is appropriate for routine TDM of TPM.

Quantification of levetiracetam in human plasma by liquid chromatography-tandem mass spectrometry: application to therapeutic drug monitoring.

A rapid, selective, reliable, precise, accurate, and reproducible tandem mass spectrometric (MS-MS) method for the quantification of levetiracetam (LEV) in human plasma using adenosine as an internal standard (IS) has been developed and validated. The drug and IS were extracted by solid phase extraction (SPE) technique and analyzed on Symmetry((R)) C(18) column (5 microm, 3.9 mm x 50 mm) using a mobile phase of methanol-water-formic acid (97:03:0.25, v/v/v) at a flow rate of 0.2 ml/min. Quantitation was achieved using a positive electrospray ionization (ESI+) interface employing multiple reaction monitoring (MRM) mode at MRM transitions m/z 171>126 and m/z 268>136 for LEV and IS, respectively. The method was validated over the concentration range of 1.0-40 microg/ml (r>0.99) with a limit of quantification of 1.0 microg/ml (R.S.D.%; 4.1 and Bias%; -9.0 to + 11.0%). Intra- and inter-run precision of LEV assay at three concentrations ranged from 0.6 to 8.9% with accuracy (bias) varied from -4.0 to 8.6% indicating good precision and accuracy. Analytical recoveries of LEV and IS from spiked human plasma were in the range of 91.7-93.4% and 80.2-84.1%, respectively. Stability of LEV in human plasma samples at different conditions showed that the drug was stable under the studied conditions. Matrix effect study showed a lack of matrix effect on mass ions of LEV and IS. The described method compared well with the commercial HPLC-UV method of Chromsystem (r(2)=0.99). The suitability of the developed method for therapeutic drug monitoring was demonstrated by measuring LEV in human plasma samples of epileptic patients treated with LEV.

Influence of famotidine on verapamil pharmacokinetics in rats.

The effect of famotidine (4 mg/kg, p.o.) on the kinetic profile of co-administered verapamil (20 mg/kg(-1), p.o.) was studied in the rat. Plasma verapamil levels were collected serially for 12 h and measured using sensitive HPLC method. The pharmacokinetic parameters (elimination half-life, area under the plasma concentration-time curve, peak plasma levels and the times to attain these plasma levels) of verapamil were evaluated in the rat. The results indicate that co-administered famotidine did not significantly alter the pharmacokinetic profile of verapamil in the rat. The present finding suggests that famotidine may safely be co-administered with verapamil but clearly further studies in human subjects are needed to reliably rule out the potential interaction of these two drugs.