Chang Qiu

Population pharmacokinetics of blonanserin in Chinese healthy volunteers and the effect of the food intake.

The aim of the study was to better understand blonanserin population pharmacokinetic (PK) characteristics in Chinese healthy subjects.

Simultaneous determination of glimepiride and pioglitazone in human plasma by liquid chromatography–tandem mass spectrometry and its application to pharmacokinetic study

The rapid, sensitive, and selective liquid chromatography-electrospray ionization-tandem mass spectrometry method (LC-ESI-MS/MS) for the simultaneous estimation and pharmacokinetic investigation of glimepiride and pioglitazone in human plasma has been developed and fully validated. Glimepiride and pioglitazone, compounds which exert synergistic effects on blood glucose control, were investigated in human plasma using deuterium-labeled analogs as internal standards (IS). Liquid-liquid extraction was carried out on 0.2 mL of human plasma using ethyl acetate, and chromatographic separation was performed on an Agilent Eclipse plus C18 column (4.6 mm × 100 mm, 3.5 μm) using a mobile phase consisting of methanol-water-formic acid (95:5:0.1, v/v/v, plus 5mM ammonium acetate) at a flow rate of 0.8 mL/min. To quantify glimepiride, pioglitazone and their IS, multiple reaction monitoring (MRM) transitions of m/z 491.2→352.2, m/z 496.2→357.2, m/z 357.2→134.2 and m/z 361.2→138.2 were performed in positive mode. The total run time was 3.0 min and the elution time was about 2.4 min. The method exhibited good separation of analytes, without interference from endogenous substances. The linear calibration curves were 0.2-250 ng/mL for glimepiride and 0.2-1,250 ng/mL for pioglitazone; the lower limit of quantification (LLOQ) was 0.2 ng/mL for both analytes. Intra- and inter-day reproducibility was less than 10% for glimepiride and less than 5% for pioglitazone, with relative errors ranging from -8.00% to 2.80% at the three concentrations of analytes used for quality control (QC). The matrix effect was negligible and recoveries were similar for each analyte and its IS. Glimepiride and pioglitazone were found to be stable under the assay conditions and the method was successfully applied to the evaluation of pharmacokinetic studies of glimepiride and pioglitazone, following oral doses of 2mg glimepiride tablets and 15 mg pioglitazone tablets to 16 healthy volunteers.

Determination of allopurinol and oxypurinol in human plasma and urine by liquid chromatography-tandem mass spectrometry

Allopurinol is used widely for the treatment of gout, but its pharmacokinetics is complex and some patients show hypersensitivity, necessitating careful monitoring and improved detection methods. In this study, a sensitive and reliable liquid chromatography-tandem mass spectrometry method was developed to determine the concentrations of allopurinol and its active metabolite oxypurinol in human plasma and urine using 2,6-dichloropurine as the internal standard (IS). Analytes and the IS were extracted from 0.5ml aliquots of plasma or urine using ethyl acetate and separated on an Agilent Eclipse Plus C18 column using methanol and ammonium formate-formic acid buffer containing 5mM ammonium formate and 0.1% formic acid (95:5, v/v) as the mobile phase (A) for allopurinol or methanol plus 5mM ammonium formate aqueous solution (95:5, v/v) as the mobile phase (B) for oxypurinol. Allopurinol was detected in positive ion mode and the analysis time was about 7min. The calibration curve was linear from 0.05 to 5μg/mL allopurinol in plasma and 0.5-30μg/mL in urine. The lower limit of quantification (LLOQ) was 0.05μg/mL in plasma and 0.5μg/mL in urine. The intra- and inter-day precision and relative errors of quality control (QC) samples were ≤11.1% for plasma and ≤ 8.7% for urine. Oxypurinol was detected in negative mode with an analysis time of about 4min. The calibration curve was linear from 0.05 to 5μg/mL in plasma (LLOQ, 0.05μg/mL) and from 1 to 50μg/mL in urine (LLOQ, 1μg/mL). The intra- and inter-day precision and relative errors were ≤7.0% for plasma and ≤9.6% for urine. This method was then successfully applied to investigate the pharmacokinetics of allopurinol and oxypurinol in humans.

Effect of grapefruit juice and food on the pharmacokinetics of pirfenidone in healthy Chinese volunteers: a diet–drug interaction study

Abstract 1. Ingestion of grapefruit juice and food could be factors affecting the pharmacokinetics of pirfenidone, a promising drug for treatment of idiopathic pulmonary fibrosis. 2. A randomized, open-label, three-period crossover study was carried out in 12 healthy Chinese male volunteers who were randomized to one of the three treatments: pirfenidone tablets (0.4 g) were orally administered to fasted or fed subjects, or with grapefruit juice. The washout period was 7 d. 3. Significantly reduced maximum plasma concentration (Cmax, 5.0 5 ± 1.39 versus 10.9 0 ± 2.94 mg·L− 1), modestly affected area-under-the-plasma concentration–time curve (AUC) from time zero to 12 h post dosing (AUC0–12 h, 21.8 9 ± 6.47 versus 26.1 6 ± 7.32 mg·h·L− 1) and delayed time to reach Cmax (Tmax) were observed in fed group compared with fasted group. Similar effects on Cmax (5.8 2 ± 1.23 versus 10.9 0 ± 2.94 mg·L− 1) and AUC0–12 h (modest but not statistically significant, 24.4 4 ± 7.40 versus 26.1 6 ± 7.32 mg·h·L− 1) were observed for grapefruit juice compared to fasted subjects. 4. Co-administration of pirfenidone with grapefruit juice resulted in modestly reduced overall oral absorption and significantly reduced peak concentrations compared to fasting, which was similar to effect of food ingestion. No adverse events were observed in the study, but relatively dramatic reduction of peak concentrations should raise concerns for clinical efficacy and safety.

A rapid LC–MS/MS quantification of peramivir using a simple and inexpensive sample precipitation: application to PK

AIM Peramivir is a newly approved selective neuraminidase inhibitor designed to inhibit influenza virus infection. METHODOLOGY/RESULTS We report a robust and sensitive method utilizing simple precipitation extraction with LC-MS/MS for the high-throughput quantification. Addition of 0.06 M of ammonium formate and 0.1% formic acid in mobile phase could help reduce the matrix effect. This method uses 100 µl of plasma and covers a linear concentration range from 5 to 10,000 ng/ml. Other validation parameters are also evaluated and meet regulatory expectations by US FDA guidelines. CONCLUSION The developed HPLC-MS/MS method has been successfully applied to support a clinical pharmacokinetic study. The strategy presented here can be applied elsewhere and may be useful for other amphiphilic drugs.

The effect of food on the pharmacokinetic properties and bioequivalence of two formulations of pitavastatin calcium in healthy Chinese male subjects

Abstract 1. Pitavastatin is an effective treatment for primary hyperlipidemia and mixed dyslipidemia. The aim of the present study was to investigate the effect of food on the pharmacokinetic properties and bioequivalence of the original, branded, formulation of pitavastatin calcium and a new generic formulation in healthy Chinese male subjects under fasting and fed conditions. 2. Under fasting and fed conditions, 90% CIs of the geometric mean of generic/branded AUC0–48 h ratios were 92.2–102.4%, 93.1–104.5%, the ratios of ln(AUC0–∞) were 92.6–103.7%, 93.2–103.5%, and ln(Cmax) ratios were 90.7–110.3%, 84.7–100.8%, respectively. The generic and branded formulations were bioequivalent in terms of rate and extent of absorption under both the conditions. The average values of AUC0–48 h, AUC0–∞ and Cmax decreased noticeably following a high-fat breakfast. Values for AUC0–48 h were 87.69% and 83.7%, values for AUC0–∞ were 87.5% and 84.6%, and values for Cmax were 45.0% and 50.4% in subjects given the generic and branded preparations, respectively. The absorption of pitavastatin calcium tablets was delayed following a high-fat meal, with Tmax increasing by up to 2.43-fold. 3. Both formulations were generally well tolerated, with no serious adverse reactions reported. The newly developed generic formulation may provide a reliable alternative to the branded tablets for patients with primary hyperlipidemia or mixed dyslipidemia.

Development and validation of a sensitive LC-MS/MS assay for the quantification of nizatidine in human plasma and urine and its application to pharmacokinetic study.

We developed and validated a high performance liquid chromatographic method coupled with triple quadrupole mass spectrometry for analysis of nizatidine in human plasma and urine. The biological samples were precipitated with methanol before separation on an Agilent Eclipse Plus C18 column (100mm×46mm, 5μm) with a mixture of methanol and water (95:5, plus 5mM ammonium formate) as the mobile phase at 0.5mL/min. Detection was performed using multiple reaction monitoring modes via electrospray ionization (ESI) at m/z 332.1→155.1 (for nizatidine) and m/z 335.1→155.1 (for [(2)H3]-nizatidine, the internal standard). The linear response range was 5-2000ng/mL and 0.5-80μg/mL for human plasma and urine, with the lower limits of quantification of 5ng/mL and 0.5μg/mL, respectively. The method was validated according to the biological method validation guidelines of the Food and Drug Administration and proved acceptable. This newly developed analytical method was successfully applied in a pharmacokinetic study following single oral administration of a 150mg nizatidine capsule in to 16 healthy Chinese subjects. Maximum and endpoint concentrations in plasma and urine were quantifiable, suggesting our method is appropriate for routine pharmacokinetic analysis.

Simultaneous determination of pirfenidone and its metabolite in human plasma by liquid chromatography-tandem mass spectrometry: application to a pharmacokinetic study.

A simple and rapid analytical method for the simultaneous determination of pirfenidone and its metabolite, 5-carboxy-pirfenidone, in human plasma using liquid chromatography-tandem mass spectrometry has been developed and validated. Aliquots of plasma (0.1 mL) containing pirfenidone and 5-carboxy-pirfenidone, as well as deuterium-labeled internal standards (ISs), were deproteinized using acetonitrile. An Agilent Zorbax Plus C18 column was used for the chromatography, with isocratic elution. The mobile phase was a mixture of acetonitrile and aqueous ammonium formate solution (5 mM) containing 0.1% formic acid (60 : 40, v/v). Using multiple reaction monitoring in positive ionization mode, transitions m/z 186.1 → 65.1, m/z 216.0 → 77.0, m/z 191.1 → 65.1 and m/z 221.0 → 81.0 were chosen to quantify pirfenidone, 5-carboxy-pirfenidone and the two ISs, respectively. The time of analysis was <3 min. The calibration curve was linear over the concentration ranges 0.005-25 μg/mL for pirfenidone, and 0.005-15 μg/mL for 5-carboxy-pirfenidone. The lower limit of quantification for both analytes was 0.005 μg/mL. The intra- and interday precision and relative errors in quality control samples were between -11.7 and 1.3% for pirfenidone and between -5.6 and 2.5% for 5-carboxy-pirfenidone, with mean recoveries ≥90%. The method that has been developed is easy to carry out, sensitive and rapid, and has been successfully used to investigate the pharmacokinetics of pirfenidone in healthy human volunteers.

Elevated PT, APPT and PT/INR possibly associated with doxycycline and cefoperazone co‐administration: A case report

Little is known regarding changes in blood coagulation parameters associated with tetracycline antibiotics. We report a possible case of elevated PT, APPT and PT/INR associated with doxycycline and cefoperazone co‐administration.

Rhabdomyolysis and elevated liver enzymes after rapid correction of hyponatremia due to pneumonia and concurrent use of aripiprazole: A case report

Rhabdomyolysis has been reported with rapid correction of hyponatremia, while liver aminotransferase abnormalities are rare. We report the first case of rhabdomyolysis and elevated liver enzymes after rapid correction of hyponatremia due to pneumonia and concurrent use of aripiprazole. A 54-year-old Chinese patient with schizophrenia was admitted to the emergency room due to cough, expectoration and seizures. Further diagnostic tests revealed severe hyponatremia (sodium 118.0 mmol/L) and pneumonia. Correcting hyponatraemia was first attempted with hypertonic saline. Meanwhile, cefoperazone–tazobactam was added and antipsychotics (clozapine 100 mg/day and aripiprazole 30 mg/day) were discontinued. In the first 10 hours after admission, a higher than expected increase in sodium (22 mmol/L) was noted, and sodium correction was then suspended. Although the sodium level returned to normal, his serum creatine kinase (CK) level increased to 22 862 U/L and then increased progressively to reach a peak level of 23 674 U/L (day 4). His aspartate transaminase (AST) and alanine aminotransferase (ALT) levels also increased from 44 U/L to a peak value of 531 U/L (day 1) and 36 U/L to a peak value of 158 U/L (day 6), respectively. His CK, AST and ALT levels gradually returned to normal following hepatoprotective Wuzhi tablet (Schisandra sphenanthera extract) and high-volume alkaline diuresis treatment under the close monitoring of serum sodium. Our patient had seizures due to hyponatremia, which was attributed to the syndrome of inappropriate antidiuretic hormone (SIADH). SIADH may have been a consequence of both the pneumonia and the serotonin-mediated effects of aripiprazole (Yam et al., 2013). Although it is not possible to exclude the role of seizures, the timing and the extent of CK elevation highly suggested that correcting hyponatremia rapidly was the main cause of rhabdomyolysis. Antipsychotics could also be important confounding factors by increasing amounts of serotonin, itself toxic to skeletal muscles, through blockade of 5-HT2A receptors (Tseng and Hwang, 2009). The delayed peak in CK level of 4 days after admission could be partly explained by the long elimination half-life of aripiprazole (75– 146 hours). Liver aminotransferase abnormalities, particularly AST, were also observed, and his AST level changed in concert with CK level, suggesting that skeletal muscle may be a significant source of AST elevation (Weibrecht et al., 2010). In conclusion, hyponatremia may arise during aripiprazole treatment in the context of known risk factors (i.e. pneumonia). When correcting hyponatremia, monitoring muscle and liver enzyme levels routinely is advised.