Ipilimumab, Pembrolizumab, or Nivolumab in Combination with BBI608 in Patients with Advanced Cancers Treated at MD Anderson Cancer Center.

Background: BBI608 is an investigational reactive oxygen species generator that affects several molecular pathways. We investigated BBI608 combined with immune checkpoint inhibitors in patients with advanced cancers. Methods: BBI608 (orally twice daily) was combined with ipilimumab (3 mg/kg IV every 3 weeks); pembrolizumab (2 mg/kg IV every 3 weeks); or nivolumab (3 mg/kg IV every 4 weeks). We assessed the safety, antitumor activity and the pharmacokinetic profile of BBI combined with immunotherapy. Results: From 1/2017 to 3/2017, 12 patients were treated (median age, 54 years; range, 31-78; 6 men). Treatment was overall well tolerated. No dose-limiting toxicity was observed. The most common adverse events were diarrhea (5 patients: grade (G)1-2, n = 3; G3, n = 2) and nausea (4 patients, all G1). Prolonged disease stabilization was noted in five patients treated with BBI608/nivolumab lasting for 12.1, 10.1, 8.0, 7.7 and 7.4 months. The median progression-free survival was 2.73 months. The median overall survival was 7.56 months. Four patients had prolonged overall survival (53.0, 48.7, 51.9 and 48.2 months). Conclusions: Checkpoint inhibitors combined with BBI608 were well tolerated. Several patients had prolonged disease stabilization and overall survival. Prospective studies to elucidate the mechanisms of response and resistance to BBI608 are warranted.

Napabucasin Drug-Drug Interaction Potential, Safety, Tolerability, and Pharmacokinetics Following Oral Dosing in Healthy Adult Volunteers.

Napabucasin is an orally administered reactive oxygen species generator that is bioactivated by the intracellular antioxidant nicotinamide adenine dinucleotide phosphate:quinone oxidoreductase 1. Napabucasin induces cell death in cancer cells, including cancer stem cells. This phase 1 study (NCT03411122) evaluated napabucasin drug-drug interaction potential for 7 cytochrome P450 (CYP) enzymes and the breast cancer resistance protein transporter/organic anion transporter 3. Healthy volunteers who tolerated napabucasin during period 1 received probe drugs during period 2, and in period 3 received napabucasin (240 mg twice daily; days 1-11) plus a phenotyping cocktail containing omeprazole (CYP2C19), caffeine (CYP1A2), flurbiprofen (CYP2C9), bupropion (CYP2B6), dextromethorphan (CYP2D6), midazolam (CYP3A) (all oral; day 6), intravenous midazolam (day 7), repaglinide (CYP2C8; day 8), and rosuvastatin (breast cancer resistance protein/organic anion transporter 3; day 9). Drug-drug interaction potential was evaluated in 17 of 30 enrolled volunteers. Napabucasin coadministration increased the area under the plasma concentration-time curve from time 0 extrapolated to infinity (geometric mean ratio [90% confidence interval]) of caffeine (124% [109.0%-141.4%]), intravenous midazolam (118% [94.4%-147.3%]), repaglinide (127% [104.7%-153.3%]), and rosuvastatin (213% [42.5%-1068.3%]) and decreased the area under the plasma concentration-time curve from time 0 extrapolated to infinity of dextromethorphan (71% [47.1%-108.3%]), bupropion (79% [64.6%-97.0%]), and hydroxybupropion (45% [15.7%-129.6%]). No serious adverse events/deaths were reported. Generally, napabucasin is not expected to induce/inhibit drug clearance to a clinically meaningful degree.

Mass balance and pharmacokinetics of an oral dose of 14 C-napabucasin in healthy adult male subjects.

This phase 1, open-label study assessed14 C-napabucasin absorption, metabolism, and excretion, napabucasin pharmacokinetics, and napabucasin metabolites (primary objectives); safety/tolerability were also evaluated. Eight healthy males (18-45 years) received a single oral 240-mg napabucasin dose containing ~100 µCi14 C-napabucasin. Napabucasin was absorbed and metabolized to dihydro-napabucasin (M1; an active metabolite [12.57-fold less activity than napabucasin]), the sole major circulating metabolite (median time to peak concentration: 2.75 and 2.25 h, respectively). M1 plasma concentration versus time profiles generally mirrored napabucasin; similar arithmetic mean half-lives (7.14 and 7.92 h, respectively) suggest M1 formation was rate limiting. Napabucasin systemic exposure (per Cmax and AUC) was higher than M1. The total radioactivity (TRA) whole blood:plasma ratio (AUClast : 0.376; Cmax : 0.525) indicated circulating drug-related compounds were essentially confined to plasma. Mean TRA recovery was 81.1% (feces, 57.2%; urine, 23.8%; expired air, negligible). Unlabeled napabucasin and M1 recovered in urine accounted for 13.9% and 11.0% of the dose (sum similar to urine TRA recovered); apparent renal clearance was 8.24 and 7.98 L/h. No uniquely human or disproportionate metabolite was quantified. Secondary glucuronide and sulfate conjugates were common urinary metabolites, suggesting napabucasin was mainly cleared by reductive metabolism. All subjects experienced mild treatment-emergent adverse events (TEAEs), the majority related to napabucasin. The most commonly reported TEAEs were gastrointestinal disorders. There were no clinically significant laboratory, vital sign, electrocardiogram, or physical examination changes. Napabucasin was absorbed, metabolized to M1 as the sole major circulating metabolite, and primarily excreted via feces. A single oral 240-mg dose was generally well tolerated.

A phase I and pharmacokinetic study of ganetespib (STA-9090) in advanced hepatocellular carcinoma.

BACKGROUND: Ganetespib (STA-9090) is an Hsp90 inhibitor that downregulates VEGFR, c-MET, HER2, IGF-IR, EGFR, and other Hsp90 client proteins involved in hepatocarcinogenesis, thereby making it an attractive therapy for HCC. This Phase I study was performed to establish the safety, tolerability, recommended Phase 2 dose (RP2D), and preliminary clinical activity of ganetespib in previously treated patients with advanced HCC. METHODS: Patients with advanced HCC, Child-Pugh A cirrhosis, progression on or intolerance to sorafenib, and ECOG PS ≤ 1 were enrolled in a standard 3x3 dose escalation study at doses of 100 mg/m(2), 150 mg/m(2), and 200 mg/m(2) IV given on days 1, 8, and 15 of each 28-day cycle. Objective response by RECIST version 1.1 criteria was evaluated by CT/MRI every 8 weeks. RESULTS: Fourteen patients were enrolled in this trial and received at least one dose of the study drug. Of the 14 patients: median age, 57 years old; male 71 %; Asian 36 %; HCC etiology (HBV 36 %, HCV 43 %, Hemachromatosis 7 %, unknown 21 %); Child Pugh Class (A 93 %, B 7 %); median number of prior treatments 2; median baseline AFP 70.1 ng/mL. The RP2D was determined to be 200 mg/m(2). The most commonly seen AEs were diarrhea (93 %), fatigue (71 %), AST elevation (64 %), and hyperglycemia (64 %). The most common Gr 3/4 AEs were hyperglycemia (21 %) and lipasemia (21 %). One (7 %) patient had a fatal AE, septic shock, within 30 days of receiving the study drug. One dose-limiting toxicity, grade 3 lipasemia, was observed at the 100 mg/m(2) dose. Pharmacokinetics studies showed a t1/2, CL, Tmax, and Vss of 6.45 h, 48.28 L/h (25.56 L/h/m(2)), 0.76 h, and 191 L (100.4 L/m(2)), respectively. No objective responses were seen; one patient (7 %) had stable disease at 16 weeks. Median time to progression was 1.8 months, and median overall survival was 7.2 months. CONCLUSION: Ganetespib had a manageable safety profile in patients with advanced HCC who had progressed on at least one line of systemic therapy. The pharmacokinetic profile showed that ganetespib exposure in patients with mild hepatic dysfunction is similar to that seen in patients with normal liver function. Ganetespib showed limited clinical benefit in patients with advanced HCC in this phase I trial.

A first in human, safety, pharmacokinetics, and clinical activity phase I study of once weekly administration of the Hsp90 inhibitor ganetespib (STA-9090) in patients with solid malignancies.

BACKGROUND: This phase I study investigated the maximum tolerated dose (MTD), safety, pharmacokinetics and antitumor activity of ganetespib in patients with solid malignancies. METHODS: Patients were enrolled in cohorts of escalating ganetespib doses, given as 1 hour IV infusion, once weekly for 3 weeks, followed by a 1-week rest until disease progression or unacceptable toxicity. Endpoints included safety, pharmacokinetic and pharmacodynamic parameters and preliminary clinical activity. RESULTS: Fifty-three patients were treated at doses escalating from 7 to 259 mg/m(2). The most common adverse events were Grade 1 and 2 diarrhea, fatigue, nausea or vomiting. Dose-limiting toxicities (DLT) observed were: one Grade 3 amylase elevation (150 mg/m(2)), one Grade 3 diarrhea and one Grade 3 and one Grade 4 asthenia (259 mg/m(2)). The MTD was 216 mg/m(2) and the recommended phase 2 dose was established at 200 mg/m(2) given IV at Days 1, 8, and 15 every 4 weeks. There was a linear relationship between dose and exposure. Plasma HSP70 protein levels remained elevated for over a week post treatment. Disease control rate (objective response and stable disease at ≥ 16 weeks) was 24.4%. CONCLUSIONS: Ganetespib is well tolerated as a weekly infusion for 3 of every 4 weeks cycle. The recommended phase II dose is 200 mg/m(2), and is associated with an acceptable tolerability profile. TRIAL REGISTRATION: NCT00687934.

Pharmacokinetic and pharmacodynamic study of two doses of bortezomib in patients with relapsed multiple myeloma.

PURPOSE: Characterize bortezomib pharmacokinetics/pharmacodynamics in relapsed myeloma patients after single and repeat intravenous administration at two doses. METHODS: Forty-two patients were randomized to receive bortezomib 1.0 or 1.3 mg/m(2), days 1, 4, 8, 11, for up to eight 21-day treatment cycles (n = 21, each dose group). Serial blood samples for pharmacokinetic/pharmacodynamic analysis were taken on days 1 and 11, cycles 1 and 3. Observational efficacy and safety data were collected. RESULTS: Twelve patients in each dose group were evaluable for pharmacokinetics/pharmacodynamics. Plasma clearance decreased with repeat dosing (102-112 L/h for first dose; 15-32 L/h following repeat dosing), with associated increases in systemic exposure and terminal half-life. Systemic exposures of bortezomib were similar between dose groups considering the relatively narrow dose range and the observed pharmacokinetic variability, although there was no readily apparent deviation from dose-proportionality. Blood 20S proteasome inhibition profiles were similar between groups with mean maximum inhibition ranging from 70 to 84% and decreasing toward baseline over the dosing interval. Response rate (all 42 patients) was 50%, including 7% complete responses. The safety profile was consistent with the predictable and manageable profile previously established; data suggested milder toxicity in the 1.0 mg/m(2) group. CONCLUSIONS: Bortezomib pharmacokinetics change with repeat dose administration, characterized by a reduction in plasma clearance and associated increase in systemic exposure. Bortezomib is pharmacodynamically active and tolerable at 1.0 and 1.3 mg/m(2) doses, with recovery toward baseline blood proteasome activity over the dosing interval following repeat dose administration, supporting the current clinical dosing regimen.

MLN3897 plus methotrexate in patients with rheumatoid arthritis: safety, efficacy, pharmacokinetics, and pharmacodynamics of an oral CCR1 antagonist in a phase IIa, double-blind, placebo-controlled, randomized, proof-of-concept study.

OBJECTIVE: To assess the efficacy, safety, pharmacokinetics, and pharmacodynamics of the CC chemokine receptor CCR1 antagonist MLN3897 in patients with rheumatoid arthritis (RA) receiving methotrexate (MTX). METHODS: In this phase IIa, proof-of-concept study, patients meeting the American College of Rheumatology (ACR) criteria for RA who had been taking MTX for >or=6 months with evidence of active disease were randomly assigned to receive either 10 mg oral MLN3897 or matching placebo once daily for 12 weeks (days 1-83) while continuing to receive MTX once a week. Clinical assessments, safety monitoring, and sampling for pharmacokinetic and pharmacodynamic analyses were performed throughout the study. The primary efficacy end point was the difference in the percentage of patients meeting the ACR 20% improvement criteria (achieving an ACR20 response) on day 84 in the MLN3897-treated group compared with that in the placebo-treated group. RESULTS: MLN3897 was well tolerated, with no evidence of systemic immunosuppression. In the intent-to-treat population, there was no significant difference in day 84 ACR20 response rates between MLN3897-treated patients and placebo-treated patients (35% versus 33%, respectively; P=0.72). Results were similar for the per-protocol population. Pharmacokinetic analyses demonstrated no interactions between MLN3897 and MTX. MLN3897 was associated with a high degree of CCR1 occupancy (>or=90% on days 28, 56, and 84 in 82% of patients, by macrophage inflammatory protein 1alpha internalization assay). CONCLUSION: MLN3897 at a concentration of 10 mg once daily had no discernible activity in patients with RA who were also receiving MTX. The results suggest that CCR1 antagonism is unlikely to be a viable strategy for the treatment of RA when used in isolation at the receptor occupancy levels reached in this study.

Effect of the CYP3A inhibitor ketoconazole on the pharmacokinetics and pharmacodynamics of bortezomib in patients with advanced solid tumors: a prospective, multicenter, open-label, randomized, two-way crossover drug-drug interaction study.

BACKGROUND: The proteasome inhibitor bortezomib undergoes oxidative biotransformation via multiple cytochrome P450 (CYP) enzymes, with CYP3A4 identified as a partial, yet potentially important, contributor based on in vitro drug metabolism studies. OBJECTIVE: The aim of this study was to assess the effect of concomitant administration of ketoconazole on the pharmacokinetics (PK) and pharmacodynamics (PD) of bortezomib. METHODS: This was a prospective, multicenter, open-label, randomized, multiple-dose, 2-way crossover study in patients with advanced solid tumors. All patients received bortezomib 1.0 mg/m(2) IV (on days 1, 4, 8, and 11 of two 21-day cycles) and were randomized to receive concomitant ketoconazole 400 mg on days 6, 7, 8, and 9 of cycle 1 or 2. Serial blood samples were collected over the day-8 dosing interval (immediately prior to bortezomib administration, and from 5 minutes to 72 hours after administration) in cycles 1 and 2 for measurement of plasma bortezomib concentrations for noncompartmental PK analysis and blood 20S proteasome inhibition for PD analysis. All adverse events (AEs) were recorded during each cycle including serious AEs and all neurotoxicity events for up to 30 days after the last dose of bortezomib. RESULTS: Twenty-one patients (median age, 57 years; sex, 67% male; race, 86% white; median body surface area, 2.01 m(2)) were randomized to treatment. Twelve patients completed the protocol-specified dosing and PK sampling in both cycles 1 and 2. Assessment of the effect of ketoconazole on bortezomib PK and PD was based on data in these 12 PK-evaluable patients. The ratio of geometric mean bortezomib AUC(0-tlast)(AUC from time 0 to last quantifiable concentration) for bortezomib plus ketoconazole versus bortezomib alone was 1.352 (90% CI, 1.032-1.772). Consistent with this observed mean increase in bortezomib exposure, concomitant administration of ketoconazole was associated with a corresponding increase (24%-46%) in the blood proteasome inhibitory effect. CONCLUSION: Concomitant administration of the CYP3A inhibitor ketoconazole with bortezomib resulted in a mean increase of 35% in bortezomib exposure. ClinicalTrials.gov identifier: NCT00129207.

Phase 1 clinical results with tandutinib (MLN518), a novel FLT3 antagonist, in patients with acute myelogenous leukemia or high-risk myelodysplastic syndrome: safety, pharmacokinetics, and pharmacodynamics.

Tandutinib (MLN518/CT53518) is a novel quinazoline-based inhibitor of the type III receptor tyrosine kinases: FMS-like tyrosine kinase 3 (FLT3), platelet-derived growth factor receptor (PDGFR), and KIT. Because of the correlation between FLT3 internal tandem duplication (ITD) mutations and poor prognosis in acute myelogenous leukemia (AML), we conducted a phase 1 trial of tandutinib in 40 patients with either AML or high-risk myelodysplastic syndrome (MDS). Tandutinib was given orally in doses ranging from 50 mg to 700 mg twice daily The principal dose-limiting toxicity (DLT) of tandutinib was reversible generalized muscular weakness, fatigue, or both, occurring at doses of 525 mg and 700 mg twice daily. Tandutinib's pharmacokinetics were characterized by slow elimination, with achievement of steady-state plasma concentrations requiring greater than 1 week of dosing. Western blotting showed that tandutinib inhibited phosphorylation of FLT3 in circulating leukemic blasts. Eight patients had FLT3-ITD mutations; 5 of these were evaluable for assessment of tandutinib's antileukemic effect. Two of the 5 patients, treated at 525 mg and 700 mg twice daily, showed evidence of antileukemic activity, with decreases in both peripheral and bone marrow blasts. Tandutinib at the MTD (525 mg twice daily) should be evaluated more extensively in patients with AML with FLT3-ITD mutations to better define its antileukemic activity.

Comparison of the pharmacokinetics of lansoprazole 15- and 30-mg sachets for suspension versus intact capsules.

OBJECTIVE: The pharmacokinetic profiles of single doses of lansoprazole 15- and 30-mg sachets for suspension were compared with those of corresponding doses of lansoprazole oral capsules. METHODS: Healthy adult male and female subjects were randomized (1:1 ratio) into 2 Phase 1, open-label, single-dose, 2-sequence, 2-period complete crossover studies. In the first study, each subject received 1 lansoprazole 15-mg sachet mixed with water and 1 lansoprazole 15-mg oral capsule; in the second study, each subject received 1 lansoprazole 30-mg sachet mixed with water and 1 lansoprazole 30-mg oral capsule. Administration of the 2 formulations was separated by a washout period of > or =7 days. Blood samples were collected before and after each administration to assess the pharmacokinetic parameters of lansoprazole and bioequivalence between suspension and capsule. RESULTS: Thirty-six subjects (19 males, 17 females) with a mean (SD) age of 32.0 (9.6) years and mean (SD) body weight of 68.6 (10.5) kg received lansoprazole 15 mg. Thirty-six subjects (22 males, 14 females) with a mean (SD) age of 38.0 (8.3) years and mean (SD) body weight of 75.1 (9.7) kg received lansoprazole 30 mg. The pharmacokinetic parameters of the 15- and 30-mg lansoprazole sachets for suspension were similar to those of the corresponding doses of the oral capsules. The mean (SD) values for C(max) and AUC from time 0 to infinity (AUC(0-infinity) for the lansoprazole 15-mg sachet (591.9 [242.3] ng/mL and 1614 [2065] ng.h/mL, respectively) did not differ significantly from those for the lansoprazole 15-mg capsules (578.6 [275.2] ng/mL and 1620 [2290] ng.h/mL, respectively). These parameters also did not differ significantly between the lansoprazole 30-mg sachet and 30-mg capsule: mean (SD) C(max), 1103 (428.3) and 1077 (465.6) ng/mL, respectively; mean (SD) AUC(0-infinity), 2655 (1338) and 2669 (1311) ng.h/mL, respectively. The 90% Cls for C(max) and AUC(0-infinity) ratios were contained within the 0.80 to 1.25 equivalence range, supporting bioequivalence. CONCLUSIONS: These findings suggest that the 15- and 30-mg lansoprazole sachets for suspension are bioequivalent to the corresponding doses of oral capsules. The sachet for suspension may provide an alternative route of administration to patients who have difficulty swallowing solid oral formulations.

Lansoprazole in adolescents with gastroesophageal reflux disease: pharmacokinetics, pharmacodynamics, symptom relief efficacy, and tolerability.

OBJECTIVES: To evaluate the pharmacokinetics, pharmacodynamics, symptom relief efficacy, and tolerability of lansoprazole in adolescents between 12 and 17 years of age with gastroesophageal reflux disease (GERD). METHODS: Adolescents with symptomatic, endoscopically and/or histologically proven GERD were enrolled in this multicenter, double-blind trial and randomized to lansoprazole 15 mg or 30 mg once daily for 5 days. RESULTS: Sixty-three adolescents were enrolled in the study. After lansoprazole administration, T(max) occurred at 1.6 hours in those treated with lansoprazole 15 mg and at 1.7 hours in those treated with lansoprazole 30 mg. Dose-proportional increases in lansoprazole C(max) and AUC were observed in the treatment groups. Age, weight, and gender had no significant effect on T(max), C(max), or AUC. Lansoprazole produced significant increases (P < or = 0.05) in mean 24-hour intragastric pH and the percentages of time intragastric pH was above 3 and 4. The majority of adolescents treated with lansoprazole 15 mg (69%, 22/32) or lansoprazole 30 mg (74%, 23/31) demonstrated improvement in their reflux symptoms after 5 days of treatment. Adolescents in both dosage groups exhibited reductions from baseline in the percentage of days and nights with heartburn (or other predominant symptom of GERD), the severity of heartburn, the percentage of days antacids were used, and the number of antacid tablets used per day. Pharyngitis and headache were the most commonly reported side effects among adolescents treated with lansoprazole 15 mg and 30 mg, respectively. Five patients experienced adverse events considered to be possibly treatment-related. One patient with a history of environmental allergies experienced a mild allergic reaction after 3 days of treatment with lansoprazole 15 mg. Among those treated with lansoprazole 30 mg, 4 patients each reported one occurrence of pain (toothache), diarrhea, dizziness, and rash. CONCLUSION: The pharmacokinetic parameters of lansoprazole observed in this study of adolescents are similar to those observed in studies of healthy adults. Lansoprazole 15 mg or 30 mg once daily for 5 days produces significant increases in intragastric pH, effectively relieves symptoms of reflux disease, and is well tolerated in adolescents with GERD.

Pharmacokinetics and pharmacodynamics of lansoprazole in children with gastroesophageal reflux disease.

OBJECTIVES: To evaluate the pharmacokinetics and pharmacodynamics of lansoprazole in children between 1 and 11 years of age with gastroesophageal reflux disease (GERD). METHODS: In a multicenter, open-label trial of pediatric patients with symptomatic GERD, children were assigned, based on their weight, to receive lansoprazole 15 mg (patients weighing < or = 30 kg) or lansoprazole 30 mg (patients weighing > 30 kg) once daily. The effects of lansoprazole on 24-hour median intragastric pH, the percentages of time intragastric pH was above 3 and 4, and pharmacokinetic parameters were assessed at the day-5 visit and compared to baseline. RESULTS: Sixty-six children were enrolled in the study. Mean lansoprazole C(max) values of 790.9 ng/mL and 898.5 ng/mL and T(max) values of 1.5 hours and 1.7 hours were observed in the < or = 30 kg and the > 30 kg body weight treatment groups, respectively. AUC0-24 values of 1707 ng x h/mL and 1883 ng x h/mL and T1/2 values of 0.68 hours and 0.71 hours were observed in the < or = 30 kg and > 30 kg lansoprazole body weight treatment groups, respectively. There was no statistical significant difference in AUC0-24 between the two groups (P = 0.2571). After 5 days of treatment lansoprazole produced significant increases in patients' 24-hour mean intragastric pH and the percentages of time intragastric pH was above 3 and 4 compared to baseline. CONCLUSION: The observed pharmacokinetic properties of lansoprazole in children between 1 and 11 years of age with GERD were similar to those previously observed in healthy adult subjects. Lansoprazole significantly increased the mean 24-hour intragastric pH and the percentages of time intragastric pH was above 3 and 4 when children were dosed with either 15 or 30 mg according to body weight.

The Effects of Lansoprazole on the Disposition of Antipyrine and Indocyanine Green in Normal Human Subjects.

This study was designed to evaluate the potential effects of acute and chronic daily oral doses of lansoprazole (60 mg) on the disposition of antipyrine, an almost completely metabolized low hepatic extraction compound, and indocyanine green, a hepatically secreted compound with high extraction ratio. The study utilized a randomized, placebo-controlled, double-blind, two-period crossover design. Sixteen of 18 subjects completed all phases of the study. Both antipyrine (10 mg kg(minus sign1)) and indocyanine green (0.5 mg kg(minus sign1)) were administered as single intravenous bolus doses on Days 1 and 7 of lansoprazole or placebo dosing. Acute exposure to lansoprazole had no statistically significant effects on the plasma pharmacokinetics of indocyanine green or antipyrine. After the seventh dose, there was a small but statistically significant reductions in indocyanine green total body clearance (CL), and elimination rate constant of 10.6% and 8%, respectively. Additionally, a small statistically significant reduction (8.6%) in antipyrine volume of distribution was detected. No other plasma antipyrine pharmacokinetic parameters were changed with concomitant lansoprazole administration. About a 12% increase in the recovery of one of the major antipyrine urine metabolites (NORA) was detected. Overall, this study demonstrates little or no effect of lansoprazole on the pharmacokinetics of antipyrine and indocyanine green.