Noncompartmental Pharmacokinetic Parameters Research Articles

Genotype-based tacrolimus dosing guidelines: with or without CYP3A4*22?

To test the relevance of revisiting the genotype classification based on CYP3A5*3 solely by incorporating CYP3A4*22 information. Discriminant analysis of principal component was performed to evaluate the relevance of either the CYP3A (CYP3A5+CYP3A4 genotypes) or CYP3A5*3 classification variables. This analysis was based on a linear combination of noncompartmental pharmacokinetics parameters. Discriminant analysis of principal component gave better results with CYP3A compared with CYP3A5*3 clustering. The centroid means of the pharmacokinetics variables were significantly different with CYP3A genotype clustering (p=0.04) but not with CYP3A5*3 solely (p=0.06). Canonical plots reveal a better delimitation of clusters with CYP3A genotype compared with CYP3A5*3 and the reciever operating characteristic curves confirm this better discriminative power. We provide strong arguments of incorporating CYP3A4*22 genotype in practice to fine-tune the existing Clinical Phamacogenetics Implementation Consortium guidelines in the Caucasian population.

Diclofenac sex-divergent drug-drug interaction with Sunitinib: pharmacokinetics and tissue distribution in male and female mice.

Coadministration of diclofenac and sunitinib, tyrosine kinase inhibitor, led to sex-divergent pharmacokinetic drug-drug interaction outcomes. Male and female mice were administered 60mg/kg PO sunitinib alone (control groups) or with 30mg/kg PO diclofenac. Sunitinib concentration in plasma, brain, kidney and liver were determined by HPLC and non-compartmental pharmacokinetic parameters calculated. In male mice, diclofenac decreased AUC0→∞ 38% in plasma (p<0.05) and 24% in liver (p<0.001) and 23% in kidney (p<0.001). However, AUC0→∞ remained unchanged in plasma and increased 41% in kidney (p<0.001) of female mice. In brain, sunitinib exposure decreased 46% (p<0.001) and 32% (p<0.001) in male and female brain respectively. Mechanistically, diclofenac increased the liver uptake efficiency in male (27%, p<0.05) and female (48%, p<0.001) mice and 30% in kidney (p<0.05) of male mice, probably owing to effects on efflux transporters. Sunitinib displayed sex-divergent DDI with diclofenac with probable clinical translatability due to potential different effects in male and female patients requiring careful selection of the NSAID and advanced TDM to implement a personalized treatment.

Toxicity, pharmacokinetics and metabolism of a novel inhibitor of IL-6-induced STAT3 activation.

The oncogenic transcription factor signal transducer and activator of transcription 3 (STAT3) promotes gene transcription involved in cancer, and its activation by IL-6 is found in head and neck squamous cell carcinoma. Four triazolothiadizine STAT3 pathway inhibitors were evaluated to prioritize a single compound for in vivo examination. Metabolic stability in mouse liver microsome incubation was used to evaluate four triazolothiadizine analogues, and UPCDC-10205 was administered to mice IV as single or multiple doses to evaluate toxicity. Single-dose pharmacokinetics (PK), bioavailability and metabolism were studied after IV 4mg/kg, PO 4mg/kg, or PO 30mg/kg suspension in 1% carboxymethyl cellulose. Mice were euthanized between 5min to 24h after dosing, and plasma and tissues were analyzed by LC-MS. Non-compartmental PK parameters were determined. Of the four triazolothiadizine analogues evaluated, UPCDC-10205 was metabolically most stable. The maximum soluble dose of 4mg/kg in 10% Solutol™ was not toxic to mice after single and multiple doses. PK analysis showed extensive tissue distribution and rapid plasma clearance. Bioavailability was ~5%. A direct glucuronide conjugate was identified as the major metabolite which was recapitulated in vitro. Rapid clearance of UPCDC-10205 was thought to be the result of phase II metabolism despite its favorable stability in a phase I in vitro metabolic stability assay. The direct glucuronidation explains why microsomal stability (reflective of phase I metabolism) did not translate to in vivo metabolic stability. UPCDC-10205 did not demonstrate appropriate exposure to support efficacy studies in the current formulation.

Abstract CT114: Phase Ib/II Study of RX-0201, a novel AKT-1 antisense, combined with everolimus to treat metastatic clear cell renal carcinoma - Phase Ib results

Abstract Background: RX-0201, a novel, oligonucleotide that binds native AKT-1 mRNA, prevents downstream phosphorylation to p-AKT. RX-0201, in combination with everolimus, additively inhibited Caki-1 cell growth in vitro and is in development for the treatment of metastatic clear cell renal carcinoma Methods: The phase Ib/II proof of concept, multicenter, open label study is conducted in 2 phases. The phase Ib was a dose-escalation study of RX-0201 administered in combination with everolimus. RX-0201 was administered as a continuous intravenous infusion for 14 days followed by 7 days of rest; everolimus was administered at a starting dose of 10mg once daily. Subjects were enrolled at increasing doses of RX-0201 in a modified 3+3 design. Plasma concentrations were measured in phase Ib and noncompartmental pharmacokinetic parameters were calculated using WinNonlin, Version 6.4. The dose of RX-0201 identified in phase Ib is being studied further in phase II, which is the randomized, 2-arm study of RX-0201 in combination with everolimus versus everolimus alone. Results: In the Phase Ib, seven males and 3 females, (median age 61 years) were treated with 125 mg/m⁁2/day (n = 3), 200 mg/m⁁2/day (n = 4), and 250 mg/m⁁2/day (n = 3) RX-0201 in combination with 10 mg everolimus. They received 1-3 lines of therapy prior to study entry (median = 1). The most common toxicities attributed to the combination were rash, mouth ulceration, weight loss, thrombocytopenia, facial edema, fatigue, and pruritus. No significant events were attributed to RX-0201 alone. Most events (81%) were mild or moderate in severity. Based on the tolerability, 250 mg/m⁁2/day RX-0201 dose was declared the recommended phase II dose. Three subjects in the phase Ib have experienced stable disease for 383, 191, and 122 days; a tumor burden reduction of 16 and 36% was seen in 2 subjects. RX-0201 PK demonstrated a dose proportional exposure. Conclusions: RX-0201, in combination with everolimus, appears to be safe and well tolerated in patients with metastatic renal cancer at doses up to 250 mg/m⁁2/day. Randomized phase II of this trial is currently ongoing. Citation Format: Scott Tagawa, Gurkamal S. Chatta, Sumanta K. Pal, Sanjay Goel, Reza Mazhari, Callie Heaton, Ely Benaim, Neeraj Agarwal. Phase Ib/II Study of RX-0201, a novel AKT-1 antisense, combined with everolimus to treat metastatic clear cell renal carcinoma - Phase Ib results. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr CT114.

Results from a phase 1b/2 study of RX-0201, a novel AKT-1 antisense, combined with everolimus to treat metastatic clear cell renal carcinoma.

2559Background: RX-0201 is a novel, oligonucleotide that binds native AKT-1 mRNA, preventing downstream phosphorylation to p-AKT. RX-0201, in combination with everolimus, to treat metastatic clear cell renal carcinoma. In vitro RX-0201, in combination with everolimus, additively inhibited Caki-1 cell growth. Methods: The Phase 1b/2 proof-of-concept, multicenter, open label study is conducted in 2 stages (NCT02089334). Stage 1 is a dose-escalation Phase 1b/2 study of RX-0201 in combination with everolimus (10 mg daily). RX-0201 was given as a continuous intravenous infusion for 14 days followed by 7 days of rest. Subjects were enrolled at increasing doses of RX-0201 in a 3+3 design. The target dose of RX-0201 identified in Stage 1 is being studied further evaluated in Stage 2, which is a randomized, 2-arm study of RX-0201 in combination with everolimus versus everolimus alone. Plasma concentrations were measured in Stage 1 and noncompartmental pharmacokinetic parameters were calculated using WinNonlin, Ver...

Archexin, a novel AKT-1–specific inhibitor for the treatment of metastatic renal cancer: Preliminary phase I data.

550 Background: Archexin (RX-0201) is a 20-mer oligonucleotide that is complementary to AKT-1 messenger ribonucleic acid (mRNA). The specificity of Archexin's effect on AKT-1 mRNA levels was examined in human renal cell carcinoma (von Hippel-Lindau protein-deficient renal cell carcinoma cell line) UMRC2 cells and resulted in decreased AKT-1 mRNA levels. Methods: The current study is a proof of concept phase Ib/2, multicenter, open label 2-stage study for subjects who progressed on at least 1 VEGF-targeted therapy. Stage 1 is an open-label, dose-escalation phase Ib study of Archexin administered in combination with everolimus. Archexin is administered by a 24 hour continuous intravenous infusion for 14 days followed by 7 days of rest. It is hypothesized that 250 mg/m2/day or a lower dose of Archexin will be identified as safe and well-tolerated when administered in combination with 10 mg of everolimus. The dose of Archexin identified in Stage 1 will be studied further in Stage 2 which is the randomized, open-label, 2-arm study of Archexin in combination with 10 mg of everolimus versus 10 mg of everolimus alone. Plasma concentrations were measured using a validated LC-MS/MS assay, and noncompartmental pharmacokinetic parameters were calculated using WinNonlin, Version 6.4. Results: Five subjects with metastatic clear cell renal carcinoma received 125 mg/m2/day (n = 3) or 200 mg/m2/day (n = 2) of Archexin with 10 mg of everolimus administered daily. Two subjects have had stable disease for 160 and 257 days. The most frequently reported treatment related adverse events for the combination were thrombocytopenia, vomiting and fatigue; no dose limiting toxicities have been reported currently. At all dose levels post-infusion, Archexin plasma concentrations increased rapidly and quickly reached a virtual plateau. Upon cessation of infusion on Day 14, plasma concentrations declined rapidly. Conclusions: At the dose levels tested, Archexin, in combination with everolimus, appears to be well tolerated in patients with metastatic renal cancer. Dose escalation/modification is ongoing to determine the recommended phase II dose of Archexin to be studied further in Stage 2 (randomized) when combined with everolimus. Clinical trial information: NCT02089334.

Effects of Thymoquinone on the Pharmacokinetics and Pharmacodynamics of Glibenclamide in a Rat Model

Glibenclamide and thymoquinone plasma concentrations were analysed using a sensitive RP-HPLC method, and non-compartmental model pharmacokinetic parameters were calculated. The maximum reduction in blood glucose level was observed 3 hours following glibenclamide administration, which reached 47.4% of baseline, whereas it was reduced by 53.0% to 56.2% when co-administrated with thymoquinone. Plasma concentration of glibenclamide was increased by 13.4% and 21.8% by the co-administration of thymoquinone as single and multiple doses, respectively (P<0.05). The AUC and TI/2 of glibenclamide were also increased respectively by 32.0% and 17.4% with a thymoquinone single dose, and by 52.5% and 92.8% after chronic treatment. Furthermore, diabetic rats treated with thymoquinone demonstrated a marked decrease in hepatic protein expressions of CYP3A2 and CYP2C 11 enzymes that are responsible for the metabolism of glibenclamide. The current data suggest that thymoquinone exhibits a synergistic effect with glibenclamide on glucose level, which could be explained by reducing CYP450 activity at the protein level.

Sunitinib-ibuprofen drug interaction affects the pharmacokinetics and tissue distribution of sunitinib to brain, liver, and kidney in male and female mice differently.

Tyrosine kinase inhibitor sunitinib (used in GIST, advanced RCC, and pancreatic neuroendocrine tumors) undergoes CYP3A4 metabolism and is an ABCB1B and ABCG2 efflux transporters substrate. We assessed the pharmacokinetic interaction with ibuprofen (an NSAID used by patients with cancer) in Balb/c male and female mice. Mice (study group) were coadministered (30 min apart) 30 mg/kg of ibuprofen and 60 mg/kg of sunitinib PO and compared with the control groups, which received sunitinib alone (60 mg/kg, PO). Sunitinib concentration in plasma, brain, kidney, and liver was measured by HPLC as scheduled and noncompartmental pharmacokinetic parameters estimated. In female control mice, sunitinib AUC0→∞ decreased in plasma (P < 0.05), was higher in liver and brain (P < 0.001), and lower in kidney (P < 0.001) vs. male control mice. After ibuprofen coadministration, female mice showed lower AUC0→∞ in plasma (P < 0.01), brain, liver, and kidney (all P < 0.001). However, in male mice, AUC0→∞ remained unchanged in plasma, increased in liver and kidney, and decreased in brain (all P < 0.001). The tissue-to-plasma AUC0→∞ ratio was similar between male and female control mice, but changed after ibuprofen coadministration: Male mice showed 1.6-fold higher liver-to-plasma ratio (P < 0.001) while remained unchanged in female mice and in kidney (male and female mice) but decreased 55% in brain (P < 0.05). The tissue-to-plasma partial AUC ratio, the drug tissue targeting index, and the tissue-plasma hysteresis-like plots also showed sex-based ibuprofen-sunitinib drug interaction differences. The results illustrate the relevance of this DDI on sunitinib pharmacokinetics and tissue uptake. These may be due to gender-based P450 and efflux/transporters differences.

Theophylline Pharmacokinetics in Foetal Sheep: Maternal Metabolic Capacity is the Principal Driver.

Understanding theophylline pharmacokinetics (PK) in the foetus is essential to prevent in utero toxicity and optimize prophylactic therapies. Previous studies in pregnancy have been obfuscated by maternal dosing and inadequate sampling in the foetus; both render modelling of foetal PK difficult. Six ewes carrying singleton foetuses received theophylline (60mg) into the foetal jugular vein. Blood samples were drawn from the foetus and ewe over 36hr. Serum concentrations were measured. Maternal and foetal pharmacokinetic parameters were estimated. Foetal non-compartmental pharmacokinetic parameters were as follows: half-life 7.37±1.22hr; volume of distribution 44.62±11.45L; area under the curve 14.82±2.71hr/(μg/mL); and clearance 4.15±0.70L/hr. Rapid theophylline distribution across the placenta was observed. Maternal non-compartmental pharmacokinetic parameters were as follows: half-life 6.54±2.44hr; volume of distribution 32.48±9.99L; area under the curve 16.28±4.53hr/(μg/mL); and clearance 3.69±1.47L/hr. Foetal and ewe serum concentration-time profiles were fit together into a 3-compartment population pharmacokinetic model, and parameters were as follows: central volume 1.38±0.11L; 2nd peripheral compartment volume 3.11±0.29L; 3rd peripheral compartment volume 60.14±6.02L; elimination clearance 9.89±0.90L/hr; distribution clearance between central and 2nd compartment 30.87±2.31L/hr; and distribution clearance between 2nd and 3rd compartments 13.89±1.11L/hr. Cytochrome P4501A expression was robust in maternal liver; negligible activities were observed in placenta, foetal liver and foetal kidney. In vitro protein binding of theophylline was 30% lower in foetal serum compared to maternal serum (29.7±4.4 versus 42.0±3.6%-bound). Free concentrations were lower in the foetus than in the ewe, suggesting active transport across placenta. In summary, foetal clearance of theophylline is attributable to rapid distribution into the maternal circulation across the placenta followed by greater maternal protein binding and metabolic activity.

Subcutaneous Injection Depth Does Not Affect the Pharmacokinetics or Glucodynamics of Insulin Lispro in Normal Weight or Healthy Obese Subjects.

An 8-mm needle length is commonly used for insulin injections; however, recent recommendations suggest shorter needles may help patients avoid intramuscular injections and reduce pain, while maintaining adequate glucose control. The goal of these analyses was to compare the pharmacokinetics (PK) and glucodynamics (GD) of insulin lispro after a 5-mm or an 8-mm injection depth administration in 2 populations: normal weight (study 1) or obese (study 2). In both open-label, randomized, 2-period crossover euglycemic clamp studies, subjects received single 0.25 U/kg insulin lispro doses on 2 occasions (at 5-mm and 8-mm injection depths); samples for PK and GD analyses were collected up to 6 hours postdose. Noncompartmental PK parameters AUC0-tlast, AUC0-∞, Cmax and GD parameters Gtot, Rmax, tRmax were log-transformed prior to analysis using a mixed effects model. There were no apparent differences between PK profiles at the 5-mm or 8-mm injection depth in either study, demonstrated by the ratios of geometric means of AUC0-tlast, AUC0-∞, and Cmax being close to 1, with 90% confidence intervals (CI) within (0.80, 1.25). There were no apparent differences between GD profiles at either injection depth with the ratios of Gtot and Rmax near unity and 90% CIs that included 1. In both studies, the tRmax values were similar between injection depths, with a small median of pairwise differences and a 90% CI that included zero. Injection depths in the 5-8 mm range did not affect the PK or GD of insulin lispro in normal weight or obese subjects.

Sunitinib tissue distribution changes after coadministration with ketoconazole in mice.

Sunitinib is a multitargeted tyrosine kinase inhibitor approved for gastrointestinal stromal tumor (GIST), advanced renal cell carcinoma (RCC) and pancreatic neuroendocrine tumors. It is metabolized via CYP3A4 and has low brain penetration due to efflux transporters ABCB1B and ABCG2. We studied the interaction with ketoconazole (50mg/kg), antifungal drug which shares metabolic pathways and efflux transporters, in ICR female mice after oral coadministration (30min apart) of 60mg/kg sunitinib (study group) versus sunitinib alone (control group). Plasma, liver, kidney and brain sunitinib concentrations were measured by HPLC at 2, 5, 10, 20, 40min, 1, 2, 4, 6, 12h post-sunitinib administration, and non-compartmental pharmacokinetic parameters estimated. In plasma, ketoconazole coadministration increased plasma maximum concentration (C MAX) 60%, delayed time to C MAX (T MAX); 1.6-fold greater area under the curve AUC0→∞ (p<0.001); lower apparent steady-state volume of distribution (V SS/F) and oral clearance (Cl/F) 40 and 61%, respectively; and shorter elimination half-life (t 1/2). Sunitinib exhibited extensive tissue distribution which increased after ketoconazole coadministration: total area under the curve (AUC0→∞) increased 1.8-, 2.8- and 1.2-fold in kidney, liver and brain, respectively (all p<0.001). Sunitinib presented high tissue-to-plasma AUC0→∞ ratio in liver (17.8±1.2), kidney (14.6±1.52) and brain (2.25±0.18) which was modified after coadministration: AUC0→∞ ratio increased in liver (31.4±4.7; p<0.001), kidney (17.1±2.2; p>0.05) and decreased in brain (1.70±0.23, p>0.05). The results showed a significant ketoconazole-sunitinib interaction that affected plasma, tissue pharmacokinetics and tissue uptake mechanisms. The study portrays the risk to increase toxicity and potential clinical translatability to treat tumors in tissues.

Single‐ and multiple‐dose study to evaluate pharmacokinetics, safety and tolerability in healthy volunteers: A comparison of extended‐release oxycodone with sequestered naltrexone 40 mg twice daily to oxycontin 40 mg twice daily and extended‐release oxycodone with sequestered naltrexone 80 mg once daily

AbstractALO‐02 capsules (ALO‐02) contain pellets that consist of extended‐release oxycodone that surrounds sequestered naltrexone. The primary objective was to characterize the pharmacokinetics (PK) of oxycodone following single‐ and multiple‐dose oral administration of ALO‐02 40 mg BID in healthy volunteers. Secondary objectives were to characterize (1) the PK of oxycodone following single‐ and multiple‐dose administration of a comparator OxyContin (OXY‐ER) 40 mg BID as well as an alternate regimen of ALO‐02 80 mg QD, and (2) the safety and tolerability assessments. Healthy volunteers received three treatments on a background of oral naltrexone (50 mg). Noncompartmental PK parameters were calculated for oxycodone. All 12 subjects were male with a mean age (SD, range) of 44.6 years (7.6, 25–55). Single‐dose PK results for ALO‐02 indicate that median peak plasma oxycodone concentrations were reached by 12 hours compared to 4 hours for OXY‐ER. Compared to OXY‐ER, mean dose‐normalized, single‐dose Cmax values were approximately 27% and 23% lower for ALO‐02 40 mg BID and ALO‐02 80 mg QD treatments, respectively. Following multiple doses all treatments reached steady state by 3 days. At steady state, oxycodone peak‐to‐trough fluctuation was significantly lower for ALO‐02 BID versus OXY‐ER. Adverse events were consistent with opioid therapy. ALO‐02 40 mg BID treatment provided a PK profile appropriate for around‐the‐clock treatment of chronic pain.

Is the pharmacokinetics of bupivacaine equivalent after lumbar epidural administration through a needle or a catheter in male and female adults?

We assessed possible pharmacokinetic modifications due to different epidural injection techniques using either a needle or a catheter. Adult patients (n=23) undergoing lower abdominal or lower extremity surgery were randomly assigned a single bupivacaine epidural injection anesthesia (0.5%, 15mL, 0.3mL/s) through needle or catheter device. Plasma bupivacaine concentration was quantified using a validated HPLC method and non-compartmental pharmacokinetic parameters estimated. CMAX and TMAX were similar in both groups: 952±346 ng/mL, 0.65±0.51h in the needle group; 810±307 ng/mL, 0.43±0.29h in the catheter group respectively. Plasma AUC0→∞ was also similar in both groups: 3868±1687 ngh/mL for needle versus 4096±1748 ngh/mL using catheter. The catheter group showed slower disposition than the needle group: t1/2=3.9±2.3h, MRT=6.0±3.1h versus 2.7±1.03h and 4.5±1.2h with needle administration respectively though it did not reach statistical significance, Cl/F and V/F were also similar. Lastly, female patients showed significant longer t1/2 after administration through catheter (5.7±2.0h) than needle (2.7±0.6h) group (P=0.0279). The device type does not affect the pharmacokinetics which is similar in both groups although sex-based differences might exist.

Pharmacokinetic and tissue distribution profile of curculigoside after oral and intravenously injection administration in rats by liquid chromatography–mass spectrometry

Curculigoside has an extensive pharmacological activity, including estrogen-like, improving sexual behavior, antiosteoporotic, antioxidant, immunomodulatory and neuroprotective effects. However, few investigations have been conducted about the pharmacokinetics and tissue distribution of curculigoside to better understand its behavior and action mechanism in vivo. Thus, a sensitive and reliable liquid chromatography with mass spectrometry (HPLC–MS) method was established and validated for the quantification of curculigoside in rat plasma and tissue samples. Biological samples were processed with methanol precipitation, and naringin was used as the internal standard. Chromatographic separation was performed on an Agilent XDB-C18 chromatography column (3.0mm×50mm, 1.8μm) with a mobile phase consisting of acetonitrile and 0.1% formic acid. Quantification was performed by selected ion monitoring with m/z 511.1 [M+HCO2]− for curculigoside and m/z 579.1 [M−H]− for the internal standard. The validated method was successfully applied to the pharmacokinetic and tissue distribution study of curculigoside in rats. Non-compartmental pharmacokinetic parameters indicated that curculigoside had rapid distribution, extensive tissue uptake, and poor absorption into systemic circulation. The values of absolute bioavailability were 0.38%, 0.22% and 0.27% for oral doses of 100, 200 and 400mg/kg, respectively. The results of the tissue distribution study suggested that curculigoside was distributed into the heart, lung, spleen, intestine, stomach, kidney, thymus, liver, brain, testis, and bone marrow after oral administration of 150mg/kg. In conclusion, the present study may provide a material basis for study of the pharmacological action of curculigoside, and meaningful insights into further study on clinical application.

Pharmacokinetic interaction between pyronaridine-artesunate and metoprolol.

The objectives of this study were to characterize any drug-drug interaction between the antimalarial Pyramax (pyronaridine-artesunate [PA]) and the CYP2D6 probe substrate metoprolol and to assess the safety of 60-day or 90-day PA redosing, particularly with regard to liver biochemistry parameters. Healthy adult subjects were randomized to arm A (n = 26) or arm B (n = 30), with the arm A subjects administered 100 mg metoprolol tartrate in the first period, 100 mg metoprolol tartrate with the third of three daily doses of PA in the second period, and three daily doses of PA alone in the 90-day redosing period. The arm B subjects received the three-day PA regimen in the first period, with redosing of the regimen after 60 days in the second period. The noncompartmental pharmacokinetic parameters were computed for metoprolol, its metabolite alpha-hydroxymetoprolol, and pyronaridine. The coadministration of metoprolol and PA was associated with an average 47.93% (90% confidence interval [CI], 30.52, 67.66) increase in the maximum concentration of metoprolol and a 25.60% (90% CI, 15.78, 36.25) increase in the metoprolol area under the concentration-time curve from time zero to the last quantifiable concentration obtained (AUC0-t); these increases most likely resulted from pyronaridine-mediated CYP2D6 inhibition. No interaction effect of metoprolol with pyronaridine was apparent. Following dosing with PA, some subjects experienced rises in liver function tests above the upper limit of normal during the first few days following PA administration. All such elevations resolved typically within 10 days, and up to 30 days at most. In subjects who were redosed, the incidences of alanine aminotransferase (ALT) or aspartate transaminase (AST) level elevations were similar on the first and second administrations, with no marked difference between the 60-day and 90-day redosing.

Pharmacokinetics of levodopa in patients with Parkinson disease and motor fluctuations depending on the presence of Helicobacter pylori infection.

According to recent investigations, the eradication of Helicobacter pylori (H. pylori) may influence levodopa (LD) pharmacokinetics (PK) and improve the motor function of infected patients with Parkinson disease (PD). The aim of this study was to compare PK of LD and its metabolite 3-O-methyldopa (3-OMD), between H. pylori-positive (HP+) and -negative (HP-) patients with PD and motor fluctuations. Patients with the clinical diagnosis of PD, under stable LD therapy, reporting daily motor fluctuations and who had no history of previous eradication treatment were screened for the H. pylori infection with an antigen stool test. Two groups of patients-bacteria-infected and noninfected-matched demographically and clinically, were selected for the examination of PK values. Blood samples were collected after morning oral LD dose. Noncompartmental PK parameters were computed from the LD and 3-OMD plasma concentration-time data. Interindividual variability was seen in LD absorption curve in both groups. There were no clinically significant differences in PK parameters of LD and 3-OMD. Changes of small magnitude but with possible clinical impact were found according to tmax and Cmax that tended to be lower in HP- patients and AUC0-t that was larger in the HP+ group. The Cmax value of 3-OMD was almost identical in both groups. The HP- group had smaller AUC0-∞t of 3-OMD. The H. pylori infection in PD patients with motor fluctuations, despite not significantly influencing PK parameters of LD and 3-OMD, may still have important clinical implications.

Simultaneous determination of bioactive components of Radix Angelicae Sinensis-Radix Paeoniae Alba herb couple in rat plasma and tissues by UPLC-MS/MS and its application to pharmacokinetics and tissue distribution.

A highly sensitive and rapid ultra performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) has been developed and validated for simultaneous quantification of seven components in rat plasma and five components in rat tissues after oral administration of the extracts of different combination Radix Angelicae Sinensis-Radix Paeoniae Alba herb couple and has been applied to compare the different pharmacokinetics and tissue distribution properties of these bioactive components. The extracts of Radix Angelicae Sinensis (RAS), Radix Paeoniae Alba (RPA) and Radix Angelicae Sinensis-Radix Paeoniae Alba herb couple (RRHC) were orally administrated to rats, respectively. The concentrations of ferulic acid, caffeic acid, vanillic acid, ligustilide, paeoniflorin, albiflorin and oxypaeoniflorin in rat plasma and the concentrations of ferulic acid, vanillic acid, paeoniflorin, albiflorin and oxypaeoniflorin in tissues were determined by UPLC-MS/MS. The plasma samples were pretreated by protein precipitation with methanol and the tissue samples were homogenated with water and pretreated by protein precipitation with methanol. Chromatographic separation was performed on a C18 column using 0.1% formic acid-acetonitrile as mobile phase for gradient elution. A triple quadrupole (TQ) tandem mass spectrometry equipped with an electrospray ionization source was used as detector operating both in positive and negative ionization mode and operated by multiple-reaction monitoring (MRM) scanning. Noncompartmental pharmacokinetic parameters were calculated by DAS 2.0 program. The differences between each group were compared by SPSS 16.0 with Independent-Samples T-test. The pharmacokinetic parameters (such as Cmax, Tmax, T1/2, AUC0-T, MRT0-T, Vz/F or CLz/F) of all the detected components between the single herb (RAS or RPA) and herb pair (RRHP) showed significant differences (P<0.05). It indicated that the compatibility of RAS and RPA could alter the pharmacokinetics features of each component. Tissue distribution results showed that ferulic acid, vanillic acid, paeoniflorin, albiflorin and oxypaeoniflorin mostly distributed in liver and kidney both in herb couple and single herb distributed most in liver and kidney. Compared with single herb, RRHC could increase or decrease the concentrations of five components at different time points compared with the sing herb. The results indicated the method was successfully applied to the comparative study on pharmacokinetics and tissue distribution of different combination of RRHC in rats. The compatibility of two Chinese herbs could alter the pharmacokinetics and tissue distribution properties of major bio-active components in the single herb. The results might be helpful for further investigation of compatibility mechanism of RRHC.

Cytochrome P450 3A and P-glycoprotein drug-drug interactions with voclosporin

Voclosporin is a novel calcineurin inhibitor intended for prevention of organ graft rejection and treatment of lupus nephritis. Pharmacokinetic drug interactions between voclosporin and a CYP3A inhibitor, inducer and substrate and a P-glycoprotein inhibitor and substrate were evaluated. Voclosporin 0.4 mg kg(-1) was administered to 24 subjects in each of five studies, as follows: every 12 h (Q12H) alone and concomitantly with ketoconazole 400 mg once daily (QD); single dose before and single dose after rifampin 600 mg QD; Q12H where midazolam 7.5 mg was administered as a single dose alone before voclosporin and with last the dose of voclosporin; Q12H alone and concomitantly with verapamil 80 mg every 8 h; and Q12H with digoxin 0.25 mg QD. The noncompartmental pharmacokinetic parameters maximal concentration (Cmax ) and area under the concentration-time curve (AUC) were obtained, and geometric least squares mean ratios and 90% confidence intervals were evaluated. Ketoconazole increased voclosporin Cmax (6.4-fold) and AUC (18-fold); rifampin reduced voclosporin AUC (0.9-fold); voclosporin did not change exposure of midazolam or α-hydroxy-midazolam; verapamil increased voclosporin Cmax (2.1-fold) and AUC (2.7-fold); and voclosporin increased digoxin Cmax (0.5-fold), AUC (0.25-fold) and urinary excretion (0.2-fold). Administration of voclosporin concomitantly with strong inhibitors and inducers of CYP3A resulted in increased and decreased exposures, respectively, and should be considered contraindicated. Drug-drug interactions involving voclosporin and CYP3A substrates are not expected. Administration of voclosporin concomitantly with inhibitors and substrates of P-glycoprotein resulted in increased voclosporin and substrate exposures, respectively. Appropriate concentration and safety monitoring is recommended with co-administration of voclosporin and P-glycoprotein substrates and inhibitors.

Quantification of OSU-2S, a novel derivative of FTY720, in mouse plasma by liquid chromatography–tandem mass spectrometry

OSU-2S is a novel anti-cancer and immune modulatory agent designed specifically to avert the immunosuppressive effects and related toxicities observed in clinical studies with its predecessor analog, FTY720. To characterize its preclinical pharmacokinetics, a liquid chromatography–tandem mass spectrometry (LC–MS/MS) method was developed and validated for the quantification of OSU-2S in mouse plasma. Ethyl acetate extraction of samples containing OSU-2S and the internal standard, Sph-17, was followed by separation with a 6min gradient (water/0.1% formic acid and methanol/0.1% formic acid) on a reverse-phase C18 column at room temperature. Selected reaction monitoring was used for detection on a triple quadrupole mass spectrometer with positive ionization. The assay was linear over the concentration range 3-3000ng/mL with accuracy ranging from 103 to 111%, and both within- and between-run precision (CV%) ≤11%. All stability samples were within ±15% of nominal values, and replicates were within 15% CV. The assay was successfully applied to a mouse pharmacokinetic study of OSU-2S with intravenous and intraperitoneal administration. OSU-2S non-compartmental pharmacokinetic parameters, area under the concentration–time curve, clearance, and elimination half-life were estimated at 1522hμg/L, 3.06L/h/kg and 15.6h, respectively, for intravenous injection. Systemic availability after intraperitoneal injection was approximately 46%. These data demonstrate the OSU-2S compound displays acceptable pharmacokinetic properties for further in vivo pharmacologic evaluation, which can be facilitated by the validated LC–MS/MS assay.

Pharmacokinetics and pharmacodynamic target attainment of intravenous pazufloxacin in the bile of patients undergoing biliary pancreatic surgery

The study aimed to characterize the pharmacokinetics and pharmacodynamics of pazufloxacin (PZFX) in bile and to identify optimal dosing regimens. Pazufloxacin 500 mg was administered via a 0·5-hour intravenous infusion to 10 patients with endoscopic nasal bile drainage before or after biliary pancreatic surgery. Both blood and bile samples were collected pre-dose and at the end of infusion (0·5 hours) and for up to 5 hours thereafter. Concentrations of PZFX were determined using high-performance liquid chromatography. Noncompartmental and compartmental pharmacokinetic parameters were estimated, and Monte Carlo simulation was conducted to evaluate the pharmacodynamic exposure of PZFX in bile. The bile/plasma ratios were 3·58±1·15 in the area under the drug concentration–time curve (AUC) and 2·13±0·74 in the maximum drug concentration (Cmax). The delay in the time to Cmax, from plasma to bile, was 0·75±0·18 hours The probability of attaining pharmacodynamic targets (both AUC/MIC = 100 and Cmax/MIC = 8) in bile against a minimum inhibitory concentration (MIC) of 2 mg/l was >90% when PZFX was administered by a 0·5-hour infusion with 500 mg every 8 hours or 1000 mg every 12 hours These regimens provided an adequate antibacterial effect against the most common pathogens of biliary tract infections, Escherichia coli, Klebsiella pneumoniae, and Enterobacter cloacae with their MICs<2 mg/l.