Lionel D Lewis

• Dartmouth College

Purpose Adavosertib may alter exposure to substrates of the cytochrome P450 (CYP) family of enzymes. This study assessed its effect on the pharmacokinetics of a cocktail of probe substrates for CYP3A (midazolam), CYP2C19 (omeprazole), and CYP1A2 (caffeine). Methods Period 1: patients with locally advanced or metastatic solid tumors received ‘cockt...

Purpose Adavosertib is a small-molecule, ATP-competitive inhibitor of Wee1 kinase. Molecularly targeted oncology agents have the potential to increase the risk of cardiovascular events, including prolongation of QT interval and associated cardiac arrhythmias. This study investigated the effect of adavosertib on the QTc interval in patients with adv...

Background: In the US adverse drug reactions (ADRs) are estimated to cause 100 000 fatalities and cost over $136 billion annually. A patient's genes play a significant role in their response to a drug. Pharmacogenomics aims to optimize drug choice and dose for individual patients by characterizing patients' pharmacologically relevant genes to iden...

Background: Adavosertib (AD), a selective WEE1 inhibitor, may alter exposure to compounds metabolized by cytochromes P450 (CYP); this two-period open-label study (NCT03333824) assessed the effect of AD on pharmacokinetics (PK) of probe substrates for CYP1A2 (caffeine; C), CYP2C19 (omeprazole; O) and CYP3A4 (midazolam; M). Methods: In period 1, pati...

Background: Adavosertib (AZD1775; AD), a highly selective inhibitor of WEE1 kinase, regulates S and G2/M cell-cycle checkpoints. This study (NCT03333824; art B) assessed the effect of doses of AD on the QT interval in patients (pts) with advanced solid tumors. Methods: After a 7-14-day washout from prior short-term AD exposure, pts received AD 225...

Background: Laboratorians have the opportunity to help minimize the frequency of adverse drug reactions by implementing pharmacogenomic testing and alerting care providers to possible patient/drug incompatibilities before drug treatment is initiated. Methods combining PCR with MALDI-ToF MS have allowed for sensitive, economical, and multiplexed ph...

It is well recognized that many cancers are addicted to a constant supply of fatty acids (FAs) and exhibit brisk de novo FA synthesis. Upregulation of a key lipogenic enzyme, fatty acid synthase (FASN), is a near-universal feature of human cancers and their precursor lesions, and has been associated with chemoresistance, tumor metastasis, and dimin...

Objective: This study evaluated whether S-warfarin LSMs accurately estimate CYP2C9 baseline and induction conditions in healthy adults and in advanced stage cancer patients. Materials and methods: Plasma S-warfarin concentrations from healthy adults (n=92) and in advanced stage cancer patients (n=22) were obtained from six published studies wher...

Abuse of synthetic drugs is an emerging trend in substance abuse. Identification of exposure to such chemicals is often difficult due to the paucity of specific laboratory assays. One such group of compounds is the 2C class of phenethylamines that include 2-(4-lodo-2, 5-dimethoxyphenyl)-N-I[(2-methyoxyphenyl)methyl]ethanamine, known as 251-NBOMe or...

This chapter is an overview of the principles of clinical pharmacology with a focus on oncology therapeutics. It covers the basic pharmacologic principles of pharmacokinetics and pharmacodynamics which underpin the individualization of a patient’s drug therapy and focuses on the utilization of these principles in anticancer drug therapy prescribing...

Prolonged infusion of dexmedetomidine, an α(2)-adrenoreceptor agonist anesthetic used in the intensive care unit, produces a withdrawal syndrome of sympathetic over-activity, characterized by tachycardia, hypertension and agitation, but there is no recommended standard treatment for this syndrome. We describe two patients with a clinical diagnosis...

Pazopanib, an oral inhibitor of vascular endothelial growth factor receptor, platelet-derived growth factor receptor, and c-kit kinases, inhibits multiple cytochrome P450 (CYP450) enzymes in vitro. This study in patients with advanced cancer evaluated the effect of pazopanib on CYP450 function by comparing the pharmacokinetics of CYP-specific probe...

e13525 Background: Milataxel (MXL) is a novel taxane with activity in human xenograft models against tumors resistant to paclitaxel. The primary objective of this study was to determine the MTD when MXL was given intravenously in combination with a fixed dose (AUC=6) of carboplatin (C) every 21 days in subjects with advanced malignant solid tumors....

The aims of this study were to investigate the bioequivalence of a new oral topotecan formulation (i.e., proposed commercial formulation) relative to the current oral formulation (formulation used in previous clinical trials), the effect of food on the absorption and disposition of the new oral topotecan and its safety and tolerability in patients...

2',2'-Difluorodeoxycytidine (gemcitabine), a pyrimidine nucleoside analog, is used therapeutically in the treatment of pancreatic, non-small cell lung, and breast cancer. The cytotoxic effect of gemcitabine is thought to be due to masked chain termination after the triphosphorylated anabolite of the drug is incorporated into nascent DNA strands. We...

Aplidin (plitidepsin) is a novel marine-derived antitumor agent presently undergoing phase II clinical trials in hematological malignancies and solid tumors. Lack of bone marrow toxicity has encouraged further development of this drug for treatment of leukemia and lymphoma. Multiple signaling pathways have been shown to be involved in Aplidin-induc...

3538 Background: We sought to characterize the PK and determine a tolerable dose of S in patients with HD or RD. Methods: Patients with performance status 0–2 and pathologically proven solid tumors, multiple myeloma, or non-Hodgkin’s lymphoma, for whom standard therapy was exhausted, were assigned to one of 9 cohorts: [1] Bilirubin (B) =ULN and SGO...

Ethylene glycol and methanol are toxic alcohols commonly found in a variety of commercial products. We report two cases, one associated with ethylene glycol and one with methanol poisoning, which both led to acute hemorrhagic necrosis of the basal ganglia and resulted in acute Parkinson's syndrome. It is unlikely that oxalate crystal deposition is...

Currently, the training and education of young clinical pharmacologist who represent the future of our discipline rest almost entirely on institutions/organizations with established and productive fellowship training programs. Here, we discuss the role of the American Board of Clinical Pharmacology (ABCP) in accrediting fellowship training programs...

3026 Background: We sought to determine a tolerable dose and characterize the pharmacokinetics (PK) of E in patients with HD or RD. Methods: Patients with biopsy-proven solid tumors that commonly express EGFR, refractory to or without available standard therapy, performance status 0–2, and without biliary or renal obstruction were assigned to one o...

13016 Background: NS-9 is a complex of poly-inosinate [poly(I)] and poly-cytidylate [poly(C)] in a cationic liposome and is active in vitro and in vivo. Objectives: to determine the tolerability, safety, and maximal tolerated dose (MTD), and pharmacokinetics of NS-9 by 1 hr IV infusion, given daily x5 q 28 days. Methods: A phase I dose escalation s...

3014 Background: Survivin is one of the family of inhibitor of apoptosis proteins (IAP) that suppresses apoptosis through inhibition of caspases and procaspases. Survivin is selectively expressed in most solid tumors but not normal tissues. In a PC-3 cell model YM155 inhibited survivin mRNA transcription and survivin protein expression and showed p...

Background: The Phase I drug metabolizing enzyme, CYP2D6, is highly polymorphic and metabolizes approximately 20% of therapeutic drugs. The objective of this study was to validate a CYP2D6 genotyping assay using the Nanochip® Molecular Biology Workstation (Nanogen Inc., San Diego, CA).Materials and methods: Following IRB approval, eighty DNA sample...

Background: ATP is an endogenous nucleotide. Preliminary data suggested that exogenous ATP may improve cachexia in advanced cancer patients. The major objectives of this study were to determine the tolerable dose of a weekly infusion of ATP, within the planned dose range and to investigate its effects cancer cachexia biomarkers.

BACKGROUNDATP is an endogenous nucleotide. Preliminary data suggested that exogenous ATP may improve cachexia in advanced cancer patients. The major objectives of this study were to determine the tolerable dose of a weekly infusion of ATP, within the planned dose range and to investigate its effects cancer cachexia biomarkers.METHODS This study was...

Background: ATP is an endogenous nucleotide. Preliminary data suggested that exogenous ATP may improve cachexia in advanced cancer patients. The major objectives of this study were to determine the tolerable dose of a weekly infusion of ATP, within the planned dose range and to investigate its effects cancer cachexia biomarkers.Methods: This study...

Purpose: AI-850, paclitaxel in a novel polyoxyethylated castor oil-free hydrophobic micropar- ticle delivery system, is being developed based on its favorable preclinical safety and antitumor activity profiles. The objectives of the study were to assess the feasibility and safety of adminis- tering AI-850 as a <30-min i.v. infusion without premedic...

2043 Background: Increased oral clearance (CL/F) of drugs that are CYP3A and/or P-glycoprotein (P-gp) substrates has been reported in African-American (AA) compared to Caucasian (C) patients (pts). The primary study objective was to test the hypothesis that the pharmacokinetics and pharmacodynamics of DCTX, an intravenously administered substrate f...

Although approximately 95% of lead poisoning among U.S. adults results from occupational exposure, lead poisoning also can occur from use of traditional or folk remedies. Ayurveda is a traditional form of medicine practiced in India and other South Asian countries. Ayurvedic medications can contain herbs, minerals, metals, or animal products and ar...

Haematopoietic suppression is one of the dose-limiting side effects of chronic zidovudine (AZT) therapy. We tested the hypothesis that AZT would reduce mitochondrial DNA (mtDNA) content in haematopoietic progenitors causing impaired haematopoiesis and mitochondrial dysfunction. We studied the effects of AZT 0-50 microM in vitro, on normal human CD3...

Molt-4 rho(0) (Molt-4 0 ) cells are a pyruvate and pyrimidine auxtophic cell line derived from Molt-4 cells, a T-cell lymphoblastic leukemia cell line. The |[rho]|0 mutant cells were generated by continuous long-term (28 day) incubation of Molt-4 wild-type (Molt-4 WT) cells in ethidium bromide (50ng/ml) supplemented with uridine and pyruvate. The a...

Clinical pharmacology is the branch of pharmacology that focuses on the study of drugs in humans. A comprehensive understanding of the principles of clinical pharmacology facilitates the clinician prescribing optimal therapy to an individual patient. Over the last 30 yr the clinical pharmacology of many drugs has been elucidated with advances in so...

The interaction between antibody based therapy and cytotoxic chemotherapy is complex. To explore these interactions we investigated, in vitro, the effects of IC20 growth inhibitory concentrations of taxanes on bispecific antibody-mediated tumor cell cytotoxicity. MDXH447 is a bispecific antibody with specificity for the high affinity IgG receptor (...

Clinical Pharmacology & Therapeutics (2003) 73, P68–P68; doi:

With the expiration of the patent on albuterol metered-dose inhalers (MDIs) in 1989, methods to assess in vivo bioequivalence of generic formulations required investigation. In an effort to develop a sensitive method to document bioequivalence, bronchoprovocation with methacholine chloride was used to assess the dose-response relationship of albute...

Intracellular calcium signaling plays a central role in cell proliferation. In leukemic cells, the calcium release-activated calcium channels provide a major pathway for calcium entry (I(CRAC)) perpetuating progression through the cell cycle. Although I(CRAC) is under mitochondrial regulation, targeting mitochondrial function has not been exploited...

We report a patient who ingested a 2000-mg overdose of quetiapine fumarate (Seroquel). Her maintenance medications also included risperidone, venlafaxine, topiramate, and clonazepam. On presentation, she was drowsy, but had no other significant CNS signs and no cardiac symptoms or abnormal physical signs. Approximately 2 h after the quetiapine inge...

Fractionation of IFX causes autoinduction of its metabolism via CYP3A4, while TAX is primarily metabolized by CYP2C8 but also by CYP3A4. We undertook a randomized crossover phase-I study of two TAX plus IFX treatment schedules in patients with advanced cancer. Schedule A was TAX (i.v. over 3 hrs) followed by 5 day fractionated IFX and schedule B wa...

The goal of this study was to evaluate, in patients with prostate cancer, the toxicity profile and biologic activity of the bispecific antibody MDXH210, which has specificity for the non-ligand-binding site of the high-affinity immunoglobulin G receptor (Fc gamma RI) and the extracellular domain of the HER-2/neu proto-oncogene product. Patients wit...

The FLAIR (fluid-attenuated inversion-recovery) pulse sequence has been shown to be sensitive to abnormalities of the subarachnoid space. Our clinical experience led us to investigate whether intravenously injected contrast material can affect the appearance of the subarachnoid space on FLAIR MR images. After noting unexplained high signal in the s...

Stress causes impaired performance on tests of creativity. Drugs that block beta-adrenergic receptors improve test performance in patients with test anxiety. Furthermore, catecholamine precursors (L-DOPA) reduce the flexibility of semantic networks. Our study investigated the effect of noradrenergic system modulation on cognitive flexibility in pro...

WR 6026 is an 8-aminoquinoline with activity against Pneumocystis carinii in vitro and in an animal model of P. carinii pneumonia that has predicted the clinical utility of related compounds. This study was conducted to assess the safety and tolerance of WR 6026 given once daily for 21 days to HIV-infected subjects with CD4 counts <500 cells/microl...

We previously observed that a single intravenous dose of MMC (5 or 10 mg/m2) down-regulated tumor MDR proteins in breast cancer patients. Therefore we undertook a Phase-I study of the safety, tolerability, and pharmacokinetics of MMC (3 or 5 mg/m2) given 48 h prior to 3 h paclitaxel infusions of 135, 175 or 200 mg/m2. Blood samples were taken for u...

Previous studies have suggested that in vivo granulocyte colony-stimulating factor (G-CSF) pharmacokinetics may change over time. We studied three patients treated with high-dose chemotherapy followed by autologous bone marrow transplantation (ABMT) for metastatic breast cancer after intravenous administration of recombinant human (rh) G-CSF (5 or...

Clinical Pharmacology & Therapeutics (1997) 62, 694–695; doi:

Clinical Pharmacology & Therapeutics (1997) 62, 237–240; doi:

A 31-year-old woman came to the hospital with breathlessness, confusion, and a refractory anion gap metabolic acidosis; acute renal failure subsequently developed. Her blood ethylene glycol concentration was 390 mg/L, and she was treated with an intravenous ethanol infusion and hemodialysis. During the tenth and eleventh day after admission bilater...

Sumatriptan, a 5-HT1D receptor agonist, is believed to alleviate migraine attacks by extracerebral vasoconstriction. Chest pain associated with myocardial ischemia may occur after sumatriptan administration. We investigated the effect of a single 6-mg subcutaneous dose of sumatriptan on myocardial perfusion (MP) as measured by 13NH3 positron emissi...

IFX induces its own metabolism over time, but the effect of agents such as TAX on IFX metabolism has not been defined. Therefore, we undertook a randomized crossover study of two TAX plus IFX treatment schedules, with planned dose escalation of TAX, in patients with cancer. Schedule A was TAX followed by fractionated IFX and schedule B was the drug...

MDX-210 is a bispecific antibody that binds simultaneously to type I Fc receptors for immunoglobulin G (IgG) (Fc gamma RI) and to the HER-2/neu oncogene protein product. MDX-210 effectively directs Fc gamma RI-positive effector cells such as monocytes and macrophages to phagocytose or kill tumor cells that overexpress HER-2/neu. The goals of this p...

In vitro studies of zidovudine (ZDV) phosphorylation may not accurately reflect the in vivo dose-response relationship, which is crucial to determining the relationship between ZDV exposure, efficacy, and toxicity. However, measurement of ZDV phosphorylated anabolites in peripheral blood mononuclear cells (PBMCs) from ZDV-treated human immunodefici...

Incubation of Molt-4 cells in 4 microM 2'3'-dideoxycytidine did not produce a significant change in the mitochondrial ultrastructure after 4 days; however, by 12 days, the mitochondrial ultrastructure was distorted, with condensed cristae or vacuolization, or both. Concentration-dependent decreases in both cell growth (mean 50% inhibitory concentra...

The effect of three ifosfamide/mesna regimens on urinary N-acetyl-beta-D-glucosaminidase (NAG) activity and beta-2-microglobulin (beta 2 M) was studied. All regimens produced significant increases in these urinary proteins, indicating nephrotubular damage. In regimen A (n = 15), plasma nitrobenzylpyridine (NBP) alkylating activity area under the cu...

1. We investigated the pharmacokinetics of ifosfamide 5 g m-2 given by two regimens. Six patients (one female), median age 55 (range 40-71) years, all with lung cancer received 5 g m-2 ifosfamide (median ifosfamide dose 8.95 g) as an intravenous infusion over 0.5 h with mesna. Four other cancer patients (all male) of median age 52.5 (range 23-72) y...

1. Fifteen patients received 1.5 g m-2 of ifosfamide intravenously over 0.5 h every day for 5 days. Twenty-one courses of treatment were studied. Plasma was assayed for ifosfamide by gas liquid chromatography and plasma alkylating activity was measured using the nitrobenzylpyridine (NBP) reaction. 2. A pharmacokinetic analysis revealed a significan...

Ifosfamide (IF) pharmacokinetics and the plasma (NBP)-alkylating activity were determined in 33 patients with different tumours after the administration of IF as single-agent chemotherapy. All subjects had been phenotyped for debrisoquine oxidation. There is a lack of correlation between the debrisoquine metabolic ratio (DMR) and either the total p...

Three out of nine unstable asthmatics whose asthma is subjectively and objectively better controlled on continuous subcutaneous terbutaline infusions (6-12 mg/24 hours) developed tender indurated subcutaneous swellings at the infusion site. In the two cases reported here in detail, histologically the lesions were areas of panniculitis and deep derm...

Beta-blockers not only exacerbate asthma and partially reversible airflow obstruction but may also precipitate and unmask latent asthma. Three cases illustrating this phenomenon are described. It is suggested that, in addition to questioning for symptoms of asthma and allergy, peak flow readings are recorded before starting patients on beta-blocker...

Midazolam hydrochloride is a recently introduced imidazobenzodiazepine. Its potency and rapid onset and short duration of action after a single intravenous bolus make it an ideal agent for premedication or induction in anaesthesia for short surgical, endoscopic, and dental procedures. These same pharmacokinetic features would seem to make the drug...