Abstract：
:Recent advances in in vitro metabolism methods have led to an improved ability to predict clinically relevant metabolic drug-drug interactions. To address the relationships of in vitro metabolism data and in vivo metabolism outcomes, the Office of Clinical Pharmacology and Biopharmaceutics in the Center for Drug Evaluation and Research, Food and Drug Administration, evaluated a number of recently approved new drug applications. The goal of these evaluations was to determine the contribution of in vitro metabolism data in (1) predicting in vivo drug-drug interactions, (2) determining the need to conduct an in vivo drug-drug interaction study, and (3) incorporating findings into drug product labeling. Ten cases are presented in this article. They fall into two major groups: (1) in vitro data were predictive of in vivo results, and (2) in vitro data were not predictive of in vivo results. Discussion of these cases highlights factors limiting predictability of in vivo metabolic interactions from in vitro metabolism data. The integration of these findings into drug product labeling is also discussed.
journal_name
J Clin Pharmacoljournal_title
Journal of clinical pharmacologyauthors
Davit B,Reynolds K,Yuan R,Ajayi F,Conner D,Fadiran E,Gillespie B,Sahajwalla C,Huang SM,Lesko LJdoi
10.1177/00912709922008515subject
Has Abstractpub_date
1999-09-01 00:00:00pages
899-910issue
9eissn
0091-2700issn
1552-4604journal_volume
39pub_type
杂志文章abstract：:The decrease in renal blood flow (RBF) observed in patients with hypertension can be increased with converting enzyme inhibition (CEI). It is unknown whether the decrease in RBF observed with age can also be increased with CEI. This study compared the short- and long-term effects of captopril monotherapy in young (les...
journal_title：Journal of clinical pharmacology
pub_type： 杂志文章
doi：10.1002/j.1552-4604.1991.tb01888.x
更新日期：1991-01-01 00:00:00
abstract：:This study was designed to evaluate the steady-state pharmacokinetics (PK) of estradiol and its metabolites, estrone and estrone sulfate, following application of a novel estradiol transdermal spray to healthy postmenopausal women. Participants were randomly assigned in parallel to receive 1-, 2-, or 3-spray doses (24...
journal_title：Journal of clinical pharmacology
pub_type： 杂志文章,随机对照试验
doi：10.1177/0091270009339187
更新日期：2009-09-01 00:00:00
abstract：:To investigate the impact of cytochrome P450 (CYP) genetic polymorphisms CYP2B6, CYP2C19, and CYP3A5 on mRNA expression, cyclophosphamide/4-hydroxycyclophosphamide pharmacokinetics, and treatment outcomes of the R-CHOP regimen (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) in Chinese patients ...
journal_title：Journal of clinical pharmacology
pub_type： 杂志文章
doi：10.1002/jcph.878
更新日期：2017-07-01 00:00:00
abstract：:Gender and body weight influence the pharmacokinetics and pharmacodynamics of many drugs. This pooled analysis of 17 clinical studies evaluated the effect of gender, body mass index (BMI), body weight, and lean body weight (LBW) on the pharmacokinetics of the direct renin inhibitor aliskiren in healthy volunteers (n =...
journal_title：Journal of clinical pharmacology
pub_type： 杂志文章
doi：10.1177/0091270009359525
更新日期：2010-12-01 00:00:00
abstract：:In a double-blind, randomized, crossover study in ten patients with asthma, the effects on specific airway resistance of esmolol, a new ultra-short-acting beta 1-selective adrenoceptor blocker, were compared with those of placebo. Specific airway resistance was measured during increasing doses of esmolol infusion, dur...
journal_title：Journal of clinical pharmacology
pub_type： 临床试验,杂志文章,随机对照试验
doi：10.1002/j.1552-4604.1986.tb02929.x
更新日期：1986-03-01 00:00:00
abstract：:The effects of long-term triple drug therapy on renal function in patients with moderate to severe essential hypertension have not been evaluated systematically. We prospectively studied fifteen male patients with moderate to severe essential hypertension receiving triple drug therapy (metolazone, atenolol or betaxolo...
journal_title：Journal of clinical pharmacology
pub_type： 杂志文章
doi：10.1002/j.1552-4604.1989.tb03423.x
更新日期：1989-09-01 00:00:00
abstract：:The effect of dose and gender on the pharmacokinetics (PK) and pharmacodynamics (PD) of zolpidem after administration of a buffered zolpidem sublingual tablet (ZST; Intermezzo®, Purdue Pharma L.P., Stamford, CT, USA) was evaluated in healthy non-elderly male and female volunteers. Subjects received a single morning do...
journal_title：Journal of clinical pharmacology
pub_type： 杂志文章,随机对照试验
doi：10.1002/jcph.220
更新日期：2014-03-01 00:00:00
abstract：:The in vitro plasma protein binding of warfarin was evaluated by ultrafiltration in plasma from seven normal subjects and seven patients with varying degrees of renal dysfunction. The unbound, or free, warfarin fraction was twice as high in the plasma samples withdrawn from patients with renal impairment than in the s...
journal_title：Journal of clinical pharmacology
pub_type： 杂志文章
doi：
更新日期：1976-10-01 00:00:00
abstract：:Upadacitinib is a selective Janus kinase 1 inhibitor that was recently approved for treatment of rheumatoid arthritis and is currently being evaluated for treatment of several other autoimmune diseases, including atopic dermatitis (AD). The relationships between upadacitinib plasma exposure and efficacy (assessed as E...
journal_title：Journal of clinical pharmacology
pub_type： 杂志文章
doi：10.1002/jcph.1782
更新日期：2020-11-06 00:00:00
abstract：:The effect of food on the pharmacokinetics of 15 mg oxybutynin XL was evaluated in a single-dose, randomized, crossover, open-label study in healthy volunteers. A validated, stereospecific, high-performance liquid chromatography assay was used to simultaneously determine the plasma concentrations of R- and S-oxybutyni...
journal_title：Journal of clinical pharmacology
pub_type： 临床试验,杂志文章,随机对照试验
doi：10.1177/00912700122010014
更新日期：2001-02-01 00:00:00
abstract：:Cannabinoids, including smoked marijuana and delta9-tetrahydrocannabinol (THC) (dronabinol, Marinol), have been used to treat human immunodeficiency virus-1 (HIV)-associated anorexia and weight loss. Concerns have been raised, however, that these compounds might have adverse effects on the immune system of subjects wi...
journal_title：Journal of clinical pharmacology
pub_type： 临床试验,杂志文章,随机对照试验
doi：10.1002/j.1552-4604.2002.tb06007.x
更新日期：2002-11-01 00:00:00
abstract：:After space-flights of less than ten days, orthostatic hypotension upon reentry is characterized by plasma volume depletion that may lead to activation of the Bezold-Jarisch reflex which is also considered to be the mechanism of vasovagal (neurocardiogenic) syncope. For space-flight of longer duration, loss of cardiov...
journal_title：Journal of clinical pharmacology
pub_type： 杂志文章,评审
doi：10.1002/j.1552-4604.1994.tb04988.x
更新日期：1994-05-01 00:00:00
abstract：:The cytomegalovirus (CMV) viral terminase inhibitor letermovir is indicated for prevention of CMV infection in CMV-seropositive allogeneic hematopoietic stem cell transplant recipients. In this analysis, functional variants in solute carrier organic anion transporter family member 1B1 (SLCO1B1), uridine diphosphate-gl...
journal_title：Journal of clinical pharmacology
pub_type： 杂志文章
doi：10.1002/jcph.1420
更新日期：2019-09-01 00:00:00
abstract：:This study evaluated the effects of intravitreal injection of fasudil (IVF), a Rho-kinase inhibitor, in cases of recent-onset nonarteritic anterior ischemic optic neuropathy (NAION). In this interventional case series, 13 eyes of 13 patients diagnosed with NAION within 14 days of onset were included. The affected eyes...
journal_title：Journal of clinical pharmacology
pub_type： 杂志文章
doi：10.1002/jcph.655
更新日期：2016-06-01 00:00:00
abstract：:Six healthy volunteers and six patients with asymptomatic duodenal ulcer disease received placebo or 300 mg nizatidine once at night or twice daily (morning and evening) for a week in a random, cross-over fashion. Steady-state serum nizatidine concentrations and gastric pH were measured over a 24-hour period. No signi...
journal_title：Journal of clinical pharmacology
pub_type： 临床试验,杂志文章,随机对照试验
doi：10.1002/j.1552-4604.1995.tb04029.x
更新日期：1995-11-01 00:00:00
abstract：:An open-label study evaluated the effect of steady-state venlafaxine on the single-dose pharmacokinetic profile of risperidone, a CYP2D6 substrate; its active metabolite, 9-hydroxyrisperidone; and the total active moiety (risperidone plus 9-hydroxyrisperidone). Thirty healthy subjects received a 1 mg oral dose of risp...
journal_title：Journal of clinical pharmacology
pub_type： 杂志文章
doi：
更新日期：1999-03-01 00:00:00
abstract：:The most commonly used Parkinson's disease (PD) treatment is the replacement of dopamine by its levodopa precursor (l-dopa). Monoamine oxidase-B (MAO-B) and catechol-o-methyl transferase (COMT) are enzymes involved in the metabolism and regulation of dopamine availability. In our study we investigated the possible rel...
journal_title：Journal of clinical pharmacology
pub_type： 杂志文章
doi：10.1002/jcph.1096
更新日期：2018-07-01 00:00:00
abstract：:Cefoxitin is a new semisynthetic cephamycin derivative with broad bactericidal activities. In order to determine the extent of the transplacental transfer of cefoxitin, 35 pregnant women received 1 Gm cefoxitin intramuscularly 15 to 180 minutes before normal or Caesarean delivery. Cefoxitin was measured microbiologica...
journal_title：Journal of clinical pharmacology
pub_type： 杂志文章
doi：10.1002/j.1552-4604.1981.tb05653.x
更新日期：1981-11-01 00:00:00
abstract：:In a placebo-controlled, randomized, double-blind cross-over study in 12 healthy volunteers the effect of acute alcohol intake during treatment with transdermally administered scopolamine (TTS-scopolamine) was investigated. One group of six subjects reached maximal blood alcohol concentrations (BAC) of 80 mg/dL and an...
journal_title：Journal of clinical pharmacology
pub_type： 临床试验,杂志文章,随机对照试验
doi：10.1002/j.1552-4604.1988.tb05728.x
更新日期：1988-12-01 00:00:00
abstract：:Lemborexant is a novel orexin receptor antagonist approved in the United States and Japan for the treatment of insomnia. This article describes the population pharmacokinetics (PK) of lemborexant and the relationship of its daily steady-state exposure (Cav,ss ) to the probability of most frequent treatment-emergent ad...
journal_title：Journal of clinical pharmacology
pub_type： 杂志文章
doi：10.1002/jcph.1683
更新日期：2020-12-01 00:00:00
abstract：:Antiretrovirals may influence methadone exposure in HIV-1-infected patients receiving methadone for opiate addiction. Rilpivirine is a non-nucleoside reverse transcriptase inhibitor for treating HIV-1 infection. In this open-label trial (NCT00744770), 13 HIV-negative volunteers continued on their regular stable methad...
journal_title：Journal of clinical pharmacology
pub_type： 杂志文章
doi：10.1002/jcph.222
更新日期：2014-02-01 00:00:00
abstract：:Two once-daily rivaroxaban dosing regimens were compared with warfarin for stroke prevention in patients with non-valvular atrial fibrillation in ROCKET AF: 20 mg for patients with normal/mildly impaired renal function and 15 mg for patients with moderate renal impairment. Rivaroxaban population pharmacokinetic (PK)/p...
journal_title：Journal of clinical pharmacology
pub_type： 杂志文章,多中心研究,随机对照试验
doi：10.1002/jcph.288
更新日期：2014-08-01 00:00:00
abstract：:A single-dose, randomized, double-blind study of parallel design was conducted to determine the analgesic efficacy and safety of ketorolac tromethamine in patients who experience moderate or severe pain after the surgical removal of three or more third molars, one of which was a bony-impacted mandibular molar. Meperid...
journal_title：Journal of clinical pharmacology
pub_type： 临床试验,杂志文章,随机对照试验
doi：10.1002/j.1552-4604.1992.tb03850.x
更新日期：1992-04-01 00:00:00
abstract：:The Cardiac Antiarrhythmic Suppression Trial (CAST) showed flecainide and encainide induced excess mortality compared with placebo. Labeling drugs as Class 1C is based on clinical observations, comprising measurements of the electrocardiographic parameters QRS. H-V and J-T intervals and of effective refractory period ...
journal_title：Journal of clinical pharmacology
pub_type： 杂志文章,评审
doi：10.1002/j.1552-4604.1991.tb03695.x
更新日期：1991-02-01 00:00:00
abstract：:Serial pharmacokinetic (PK) sampling in 1159 patients from TRITON-TIMI 38 was undertaken. A multilinear regression model was used to quantitatively predict prasugrel's active metabolite (Pras-AM) concentrations from its 2 downstream inactive metabolites. Population-based methods were then applied to Pras-AM concentrat...
journal_title：Journal of clinical pharmacology
pub_type： 杂志文章
doi：10.1177/0091270009337942
更新日期：2009-08-01 00:00:00
abstract：:Procainamide administration often results in excessively high serum N-acetylprocainamide (NAPA) concentrations and subtherapeutic serum procainamide concentrations. Inhibition of N-acetylation of procainamide may prevent accumulation of excessive NAPA while maintaining therapeutic serum procainamide concentrations. Th...
journal_title：Journal of clinical pharmacology
pub_type： 临床试验,杂志文章,随机对照试验
doi：10.1002/j.1552-4604.1995.tb04135.x
更新日期：1995-09-01 00:00:00
abstract：:In many industrialized nations, the elderly comprise the fastest growing subpopulation and constitute an increasing proportion of the total population compared to other age groups. The elderly use a disproportionately larger amount of health care resources since they experience a higher incidence of disease-related mo...
journal_title：Journal of clinical pharmacology
pub_type： 杂志文章,评审
doi：
更新日期：1999-11-01 00:00:00
abstract：:The chemoattractant receptor-homologous molecule expressed on T-helper 2 cells (CRTH2) is a G-protein-coupled receptor for prostaglandin D2 , a key mediator in inflammatory disorders. In this randomized, double-blind, placebo-controlled study we investigated the single- and multiple-dose tolerability, pharmacokinetics...
journal_title：Journal of clinical pharmacology
pub_type： 杂志文章,随机对照试验
doi：10.1002/jcph.478
更新日期：2015-07-01 00:00:00
abstract：:Atorvastatin is a common option among the HMG-CoA reductase inhibitors for the treatment of lipid disorders because of its excellent lipid-lowering efficacy and overall safety profile. Although these agents can rarely cause rhabdomyolysis by themselves, macrolides, among other agents, have been demonstrated to increas...
journal_title：Journal of clinical pharmacology
pub_type： 临床试验,杂志文章,随机对照试验
doi：
更新日期：2002-04-01 00:00:00
abstract：:An equation is derived to estimate mean steady state serum concentration (Css) from trough steady state serum concentration (Cmin) which can be used for drugs with either linear or nonlinear pharmacokinetic properties. In 15 subjects receiving phenytoin monotherapy, estimated Css did not differ significantly from meas...
journal_title：Journal of clinical pharmacology
pub_type： 杂志文章
doi：10.1002/j.1552-4604.1990.tb03612.x
更新日期：1990-06-01 00:00:00
