Significant Differences In AUC0 Research Articles

Impact of genetic polymorphisms on the pharmacokinetics and pharmacodynamics of lenvatinib in patients with hepatocellular carcinoma

This prospective study examined the impact of genetic polymorphisms on the pharmacokinetics and clinical efficacy and safety of lenvatinib, a substrate of ATP-binding transporters, in a cohort of 48 Japanese patients with hepatocellular carcinoma (HCC). Pharmacokinetic studies were performed at the start of lenvatinib therapy (day 1) and on day 15. The coefficients of variation in AUC0–24h of lenvatinib on days 1 and 15 were 44.0% and 52.4%, respectively. Although the ABCB1 3435C > A, 1236C > T, and 2677G>T/A polymorphisms did not influence pharmacokinetic parameters, the AUC0–24h values on days 1 and 15 of the ABCG2 C/A or A/A group were approximately 1.1-fold and 1.4-fold that in the ABCG2 C/C group (P = 0.164 and 0.024). There were no significant differences in AUC0–24h on days 1 and 15 between the responders (complete or partial response) and non-responders (stable or progressive disease). The AUC0–24h on day 15 in those developing anorexia of any grade was significantly higher than that without such development (P = 0.017). In multivariate analysis, ABCG2 421C > A C/A or A/A was significantly associated with the development of anorexia (odds ratio 9.009, P = 0.009). ABCG2 421C > A polymorphism could affect exposure to lenvatinib and the development of anorexia.

Pharmacokinetics and Safety Profile of Artesunate-Amodiaquine Coadministered with Antiretroviral Therapy in Malaria-Uninfected HIV-Positive Malawian Adults.

ABSTRACTThere are limited data on the pharmacokinetic and safety profiles of artesunate-amodiaquine in human immnunodeficiency virus-infected (HIV+) individuals receiving antiretroviral therapy. In a two-step intensive sampling pharmacokinetic trial, we compared the area under the concentration-time curve from 0 to 28 days (AUC0–28) of an active metabolite of amodiaquine, desethylamodiaquine, and treatment-emergent adverse events between antiretroviral therapy-naive HIV+ adults and those taking nevirapine and ritonavir-boosted lopinavir-based antiretroviral therapy. In step 1, malaria-uninfected adults (n = 6/arm) received half the standard adult treatment regimen of artesunate-amodiaquine. In step 2, another cohort (n = 25/arm) received the full regimen. In step 1, there were no safety signals or significant differences in desethylamodiaquine AUC0–28 among participants in the ritonavir-boosted lopinavir, nevirapine, and antiretroviral therapy-naive arms. In step 2, compared with those in the antiretroviral therapy-naive arm, participants in the ritonavir-boosted lopinavir arm had 51% lower desethylamodiaquine AUC0–28, with the following geometric means (95% confidence intervals [CIs]): 23,822 (17,458 to 32,506) versus 48,617 (40,787 to 57,950) ng · h/ml (P < 0.001). No significant differences in AUC0–28 were observed between nevirapine and antiretroviral therapy-naive arms. Treatment-emergent transaminitis was higher in the nevirapine (20% [5/25]) than the antiretroviral therapy-naive (0.0% [0/25]) arm (risk difference, 20% [95% CI, 4.3 to 35.7]; P = 0.018). The ritonavir-boosted lopinavir antiretroviral regimen was associated with reduced desethylamodiaquine exposure, which may compromise artesunate-amodiaquine's efficacy. Coadministration of nevirapine and artesunate-amodiaquine may be associated with hepatoxicity.

Pharmacokinetics of two 6-mercaptopurine liquid formulations in children with acute lymphoblastic leukemia.

A liquid formulation of 6-mercaptopurine (6-MP) was recently approved by the Food and Drug Administration (Purixan®) based on bioavailability (BA) data from healthy adults. We examined the pharmacokinetics (PK) and BA of 6-MP in children with acute lymphoblastic leukemia (ALL) comparing a marketed tablet, two extemporaneously prepared liquid formulations, and data from the approved liquid formulation. Twenty-two children (6-17 years) participated in a randomized two-way, crossover study of two cohorts. Group 1 (n = 11; five males) received a 5 mg/ml liquid formulation and the marketed 50 mg 6-MP tablet on separate occasions, and Group 2 (n = 11; five males) received a 50 mg/ml liquid formulation and the marketed tablet. The usual prescribed 6-MP dose (25-115 mg/m2 ) was given after an 8-hr fast. Serial blood samples were collected over 8 hr postdose. Plasma 6-MP concentrations were determined using a good laboratory practice (GLP)-validated liquid chromatography-tandem mass spectrometry method. PK parameters were calculated using noncompartmental analysis and compared within and between cohorts, and thiopurine methyltransferase (TPMT) genotype was analyzed. No patient had a TPMT genotype reflective of a poor metabolizer phenotype. Comparison of PK parameters between 5 and 50 mg/ml treatments revealed significant differences (P <0.05) in AUCN (where AUC is area under the curve), CmaxN , and Tmax . Comparisons within each group revealed significant differences in AUC0-∞ and Tmax in the 5 mg/ml group. Pharmacokinetic profiles of 6-MP established in healthy adults with the approved liquid formulation may not reflect the PK profile in children with ALL. Formulation-specific differences in PK may significantly impact the dose-exposure profile in these children and must be considered.

A crossover pharmacokinetic study of misoprostol by the oral, sublingual and buccal routes

Objectives: The aim of the study was to compare the pharmacokinetic parameters of 800 μg oral, sublingual and buccal misoprostol in healthy non-pregnant women. Methods: This was an open-label, randomised study with a three-way crossover design. Eighteen participants were randomly assigned to treatment sequences of 800 μg oral, sublingual and buccal misoprostol administered under fasting conditions, with a 7-day washout period. Ten participants completed all routes. The primary pharmacokinetic parameters measured were the area under the plasma misoprostol acid concentration–time curve (AUC) from dosing to last quantifiable concentration (AUC0–t), the AUC from 0 to infinity (AUC0–∞) and the maximum plasma concentration (Cmax). Secondary parameters included the plasma elimination rate constant (ke), the half-life and the mean residence time (MRT). Results: There were statistically significant differences in AUC0–∞, AUC0–t and Cmax at the p < 0.05 level for the three routes of administration. The sublingual route achieved the highest bioavailability, and the buccal route achieved the lowest peak concentration. The oral and buccal routes had a similar AUC0–∞ and the buccal route had the highest MRT and ke. There were no differences in half-lives, and no serious adverse events were reported. Conclusions: This study shows variability in Cmax and AUC by three by-mouth routes of misoprostol administration. The dose in this study was 800 μg, which is among the highest doses seen in current guidelines. These data contribute to the understanding of efficacy and safety of different routes and could provide a basis for deciding whether certain routes are preferable for particular indications.

Effect of ketoconazole administration on the pharmacokinetics (PK) and pharmacodynamics (PD) of bortezomib in patients with advanced solid tumors

13016 Background: Bortezomib (btz; VELCADE) is a first-in-class small molecule proteasome inhibitor used to treat patients with multiple myeloma and mantle cell lymphoma. In vitro and in vivo studies indicate that btz is primarily metabolized by CYP3A4 and CYP2C19. We conducted a study to evaluate the effect of inhibition of CYP3A4 with ketoconazole (keto) on the PK of btz in humans. Methods: The study enrolled patients with advanced malignancies for whom standard therapy was not available. Patients received btz 1.0mg/m2 (IV) on days 1, 4, 8, and 11 of a 21-day cycle, and were randomized to receive keto 400mg (PO) on days 6, 7, 8, and 9 of either the first or second cycle of treatment. Blood samples for plasma btz determination were collected over 72 hours following the Day 8 dose in Cycles 1 and 2. PK parameters were computed non-compartmentally. PD parameters were derived from an Emax model of percentage proteasome inhibition in whole blood. Results: Of the 21 patients enrolled, 13 had sufficient PK sampling in Cycles 1 and 2 to assess the effect of keto on the PK of btz. No statistically significant difference in AUC0–72h for btz ± keto was observed (p=0.2248). The mean AUC0–72h ratio was 1.22 (90% CI, 0.92–1.61). The exposure-PD relationships for btz ± keto were similar (Table). Adverse events were similar in the presence and absence of keto. Conclusions: Although the AUC0–72h difference was not statistically significant, the 90% CI for the AUC0–72h ratio extends beyond the FDA- specified range of 0.80–1.25 for DDI studies, precluding a declaration of no effect. The presence of a strong CYP3A4 inhibitor increased mean btz exposure by only 22% and had no apparent effect on the exposure-PD relationship. [Table: see text] No significant financial relationships to disclose.

Nelfinavir Suspension Obtained from Nelfinavir Tablets Has Equivalent Pharmacokinetic Profile

The pharmacokinetics of nelfinavir tablets (A) and an oral simplified nelfinavir suspension (B) were studied. Twelve healthy volunteers randomly received either five 250-mg nelfinavir tablets or a simplified oral suspension obtained from tablets dissolved in water (nelfinavir 1250 mg in 100 mL of water) in a single dose before being crossed over to the second treatment after a one-week washout period. Blood samples were drawn up to 24 h after drug administration. Nelfinavir concentrations in plasma were analyzed by a specific and validated reverse-phase high-performance liquid chromatography assay (HPLC) with UV detection, and pharmacokinetic values were determined. For the AUC0-∞with means±SD of 31.71±7.85, 30.88±10.28 (μg/L) respectively for treatments B and A, the ratio (FB/A) was of 1.1 with a C.I. of 0.90-1.24. For Cmax with means±SD of 3.1±0.6 (treatment B) and 3.2±0.8 mg/mL (treatment A), the ratio was 1.0. with C.I. of 0.92- 1.08. The two treatments evidenced no significant differences in AUC0-∞ and Cmax values and the two-one sided t-test showed that the two preparations are bioequivalent. There was no significant difference in Tmax between the liquid and tablets.Nelfinavir suspension might be a option for treating HIV-infected patients with swallowing disturbances or compliance problems.

Disposition of KW-4679. (1). Absorption, Distribution and Excretion of 14C-KW-4679 after Oral or Intravenous Administration to Rats.

The absorption, distribution and excretion of 14C-KW-4679 after oral or intravenous administration at a dose of 1 mg/kg were studied in male and female rats. Also the absorption and excretion of 14C-KW-4679 after oral administration at a dose of 25 mg/kg in male rats were studied.1) 14C-KW-4679 was rapidly absorbed and the extent of absorption was estimated to be 91% or higher after oral administration of 1 mg/kg. The drug was presumably absorbed mainly in the region from the duodenum to the jejunum.2) Plasma radioactivity reached Cmax at 0.5 hr after oral administration of 1 mg/kg to fasting male rats and then disappeared biexponentially with terminal half-life of 16.8 hr. By 96 hr after administration, 42.6% and 53.5% of the administered radioactivity were excreted in urine and feces, respectively. In bile, 46.0% of radioactivity was excreted by 72 hr after administration. The excretion of radioactivity in urine, feces and bile almost completed within 24 hr after administration.3) Delayed Tmax and reduced Cmax were observed after oral administration to non-fasting rats compared to fasting rats. There was no significant difference in AUC0-∞. No difference was observed in the excretion of radioactivity in urine and feces, whether animals were fasted or not.4) Larger AUC0-∞ by about 18% was obtained after oral administration to female rats as compared with male rats. A tendency of lower fecal excretion and higher urinary excretion of radioactivity was demonstrated in female rats.5) After intravenous administration of 1 mg/kg to fasting male rats, radioactivity was eliminated from plasma triexponentially with terminal half-life of 34.2 hr. By 96 hr after administration, 51.7% and 43.0%of the administered radioactivity were excreted in urine and feces, respectively.6) Radioactivity was rapidly distributed to almost all tissues after oral administration of 1 mg/kg to fasting male rats. Except digestive organs, higher than in plasma levels of radioactivity were observed in the liver, kidney and urinary bladder. The lowest level of radioactivity was observed in the brain, where the level was about 1/25 of that in plasma, among all the organs examined. Radioactivity in tissues was eliminated almost in parallel with plasma concentration.7) The radioactivity excreted in bile was reabsorbed (8.6%).8) Tmax, dose-normalized Cmax and AUC0-t of plasma radioactivity after oral administration at a dose of 25 mg/kg to fasting male rats was almost equal to that after oral administration at a dose of 1 mg/kg, respectively. Higher urinary excretion of radioactivity after 25 mg/kg dosing than that after 1 mg/kg dosing was observed.