Predicting Inhibitory Drug—Drug Interactions and Evaluating Drug Interaction Reports Using Inhibition Constants

2005 ◽  
Vol 39 (6) ◽  
pp. 1064-1072 ◽  
Author(s):  
Kenneth A Bachmann ◽  
Jeffrey D Lewis
Keyword(s):  
Cytochrome P450 ◽  
Drug Interaction ◽  
Drug Interactions ◽  
Web Sites ◽  
Case Reports ◽  
Data Extraction ◽  
Data Sources ◽  
Study Selection ◽  
Inhibitory Drug

OBJECTIVE: To review the use of inhibitory constants (Ki) determined from in vitro experiments in the prediction of the significance of inhibitory drug—drug interactions (DDIs). DATA SOURCES: Searches of MEDLINE (1966—August 2004) and manual review of journals, conference proceedings, reference textbooks, and Web sites were performed using the key search terms cytochrome P450, drug—drug interaction, inhibition constant, and Ki. STUDY SELECTION AND DATA EXTRACTION: All articles identified from the data sources were evaluated, and information deemed relevant was included for this review. DATA SYNTHESIS: The cytochrome P450 isoenzymes factor prominently in the explanation of numerous DDIs. Although the regulation of these enzymes by one drug can affect the pharmacokinetics of other drugs, the consequences may not necessarily be significant either in terms of pharmacokinetic or clinical outcomes. Yet, many DDI monographs originate as unconfirmed case reports that implicate the influence of one drug on the CYP-mediated metabolism of another, and these often uncorroborated mechanisms can eventually become regarded as dogma. One consequence of this process is the overprediction of potentially important DDIs. The pharmaceutical industry, Food and Drug Administration, and pharmaceutical scientists have developed a strategy for predicting the significance of inhibitory DDIs at the earliest possible stages of drug development based on a new chemical entity's Ki value, determined in vitro. CONCLUSIONS: We suggest that the use of Ki values of drugs purported to behave as CYP inhibitors be incorporated in the assessment of case reports that ascribe DDIs to inhibition of metabolism of one drug by another.

Macrolide Drug Interactions: An Update

2000 ◽  
Vol 34 (4) ◽  
pp. 495-513 ◽  
Author(s):  
Manjunath P Pai ◽  
Danielle M Graci ◽  
Guy W Amsden
Keyword(s):  
Cytochrome P450 ◽  
Drug Interaction ◽  
Drug Interactions ◽  
Case Reports ◽  
Data Extraction ◽  
Depth Information ◽  
Cytochrome P450 Enzyme ◽  
Medline Search ◽  
P450 Enzyme ◽  
Clinically Significant

OBJECTIVE: To describe the current drug interaction profiles for the commonly used macrolides in the US and Europe, and to comment on the clinical impact of these interactions. DATA SOURCES: A MEDLINE search (1975–1998) was performed to identify all pertinent studies, review articles, and case reports. When appropriate information was not available in the literature, data were obtained from the product manufacturers. STUDY SELECTION: All available data were reviewed to provide an unbiased account of possible drug interactions. DATA EXTRACTION: Data for some of the interactions were not available from the literature, but were available from abstracts or company-supplied materials. Although the data were not always explicit, the best attempt was made to deliver pertinent information that clinical practitioners would need to formulate practice opinions. When more in-depth information was supplied in the form of a review or study report, a thorough explanation of pertinent methodology was supplied. DATA SYNTHESIS: Several clinically significant drug interactions have been identified since the approval of erythromycin. These interactions usually were related to the inhibition of the cytochrome P450 enzyme systems, which are responsible for the metabolism of many drugs. The decreased metabolism by the macrolides has in some instances resulted in potentially severe adverse events. The development and marketing of newer macrolides are hoped to improve the drug interaction profile associated with this class. However, this has produced variable success. Some of the newer macrolides demonstrated an interaction profile similar to that of erythromycin; others have shown improved profiles. The most success in avoiding drug interactions related to the inhibition of cytochrome P450 has been through the development of the azalide subclass, of which azithromycin is the first and only to be marketed. Azithromycin has not been demonstrated to inhibit the cytochrome P450 system in studies using a human liver microsome model, and to date has produced none of the classic drug interactions characteristic of the macrolides. CONCLUSIONS: Most of the available data regarding macrolide drug interactions are from studies in healthy volunteers and case reports. These data suggest that clarithromycin appears to have an interaction profile similar to that of erythromycin. Given this similarity, it is important to consider the interaction profile of clarithromycin when using erythromycin. This is especially necessary as funds for further studies of a medication available in generic form (e.g., erythromycin) are limited. Azithromycin has produced few clinically significant interactions with any agent cleared through the cytochrome P450 enzyme system. Although the available data are promising, the final test should come from studies conducted in patients who are taking potentially interacting compounds on a chronic basis.

Macrolides Versus Azalides: A Drug Interaction Update

1995 ◽  
Vol 29 (9) ◽  
pp. 906-917 ◽  
Author(s):  
Guy W Amsden
Keyword(s):  
Drug Interaction ◽  
Drug Interactions ◽  
Case Reports ◽  
Data Extraction ◽  
Membered Ring ◽  
Depth Information ◽  
Variable Effect ◽  
Study Selection ◽  
Variable Success ◽  
Clinically Significant

Objective: To describe the current drug interaction profiles for all approved and investigational macrolide and azalide antimicrobials, and to comment on the clinical impact of these interactions when appropriate. Data Sources: MEDLINE was searched to identify all pertinent studies, review articles, and case reports from 1975 to 1995. When appropriate information was not available in the literature, data were obtained from the product manufacturers. Study Selection: All available data were reviewed to give an unbiased account of possible drug interactions. Data Extraction: Data for some of the interactions were not available from the literature, but were available from abstracts or from company-supplied materials. Although the data were not always entirely explicative, the best attempt was made to deliver the pertinent information that clinical practitioners would need to formulate practice opinions. When more in-depth information was supplied in the form of a review or study report, a thorough explanation of pertinent methodology was supplied. Data Synthesis: Since the introduction of erythromycin into clinical practice, there have been several clinically significant drug interactions identified throughout the literature associated with this drug. These interactions have been caused mostly by inhibition of the CYP3A subclass of hepatic enzymes, thereby decreasing the metabolism of any other agent given concurrently that is also cleared through this mechanism. With the development and marketing of several new macrolides, it was hoped that the drug interaction profile associated with this class would improve. This has been met with variable success. Although some of the extensions of the 14-membered ring macrolides have shown an incidence of interactions equal to that of erythromycin, others have shown improved profiles. In contrast, the 16-membered ring macrolides have demonstrated a much improved, though not absent, interaction profile. The most success in avoiding drug interactions through structure modification has been accomplished with the development of the azalide class, of which azithromycin is the first to be approved for marketing. This agent has to date produced none of the classic drug interactions that most macrolides have demonstrated in patient care. Conclusions: The introduction of new 14- and 16-membered ring macrolides appears to have had a variable effect in modifying the incidence of drug interactions associated with this class. Azithromycin, a member of the new azalide class, has to date produced fewer clinically significant interactions than other azalides with any agent that is cleared through the CYP3A system. Overall, the available data are promising, and the final test should come from conducting studies in patients who are taking potentially interacting compounds on a chronic basis, as most available data are from trials in healthy volunteers.

Isoniazid-Associated Psychosis: Case Report and Review of the Literature

1993 ◽  
Vol 27 (2) ◽  
pp. 167-170 ◽  
Author(s):  
Karen A. Pallone ◽  
Morton P. Goldman ◽  
Matthew A. Fuller
Keyword(s):  
Case Report ◽  
English Language ◽  
Case Reports ◽  
Data Extraction ◽  
Data Sources ◽  
Review Of The Literature ◽  
Data Synthesis ◽  
Medline Search ◽  
Study Selection ◽  
Language Literature

Objective To describe a case of isoniazid-associated psychosis and review the incidence of this adverse effect. Data Sources Information about the patient was obtained from the medical chart. A MEDLINE search of the English-language literature published from 1950 to 1992 was conducted and Index Medicus was manually searched for current information. Study Selection All case reports describing isoniazid-associated psychosis were reviewed. Data Extraction Studies were evaluated for the use of isoniazid, symptoms of psychosis, onset of symptoms, and dosage of isoniazid. Data Synthesis The case report is compared with others reported in the literature. The incidence of isoniazid-associated psychosis is rare. Conclusions The mechanism of isoniazid-associated psychosis is uncertain. It appears that isoniazid was associated with the psychosis evident in our patient and in the cases reviewed.

2020 FDA Drug-drug Interaction Guidance: A Comparison Analysis and Action Plan by Pharmaceutical Industrial Scientists

2020 ◽  
Vol 21 (6) ◽  
pp. 403-426 ◽  
Author(s):  
Sirimas Sudsakorn ◽  
Praveen Bahadduri ◽  
Jennifer Fretland ◽  
Chuang Lu
Keyword(s):  
Cytochrome P450 ◽  
Drug Interaction ◽  
Drug Interactions ◽  
Action Plan ◽  
European Medicines Agency ◽  
Cytochrome P450 Enzyme ◽  
Interaction Studies ◽  
P450 Enzyme ◽  
Us Fda

Background: In January 2020, the US FDA published two final guidelines, one entitled “In vitro Drug Interaction Studies - Cytochrome P450 Enzyme- and Transporter-Mediated Drug Interactions Guidance for Industry” and the other entitled “Clinical Drug Interaction Studies - Cytochrome P450 Enzyme- and Transporter-Mediated Drug Interactions Guidance for Industry”. These were updated from the 2017 draft in vitro and clinical DDI guidance. Methods: This study is aimed to provide an analysis of the updates along with a comparison of the DDI guidelines published by the European Medicines Agency (EMA) and Japanese Pharmaceuticals and Medical Devices Agency (PMDA) along with the current literature. Results: The updates were provided in the final FDA DDI guidelines and explained the rationale of those changes based on the understanding from research and literature. Furthermore, a comparison among the FDA, EMA, and PMDA DDI guidelines are presented in Tables 1, 2 and 3. Conclusion: The new 2020 clinical DDI guidance from the FDA now has even higher harmonization with the guidance (or guidelines) from the EMA and PMDA. A comparison of DDI guidance from the FDA 2017, 2020, EMA, and PMDA on CYP and transporter based DDI, mathematical models, PBPK, and clinical evaluation of DDI is presented in this review.

Rifabutin-Associated Uveitis

1995 ◽  
Vol 29 (11) ◽  
pp. 1149-1155 ◽  
Author(s):  
Alice L Tseng ◽  
Sharon L Walmsley
Keyword(s):  
Adverse Event ◽  
Drug Interactions ◽  
English Language ◽  
Case Reports ◽  
Data Extraction ◽  
Signs And Symptoms ◽  
Medline Search ◽  
Concurrent Therapy ◽  
Study Selection ◽  
Tolerance Study

Objective: To review rifabutin-associated uveitis and discuss the mechanism and potential role of drug interactions with clarithromycin and fluconazole in contributing to this adverse event. Data Sources: A MEDLINE search (1991 through September 1994) of English-language literature using the main MeSH headings “rifabutin” and “uveitis” and the subheadings “adverse effects” and “chemically induced.” Relevant articles also were selected from references of identified articles. Abstracts from recent medical conferences of infectious diseases, pharmacology, and HIV were screened for additional data. Study Selection and Data Extraction: All articles and abstracts reporting uveitis potentially related to rifabutin were considered for inclusion. Fifty-four cases were identified. Pertinent information from the case reports, as judged by the authors, was selected and synthesized for discussion. Data Synthesis: Rifabutin is being prescribed increasingly for the treatment and prophylaxis of Mycobacterium avium complex (MAC) infection in the HIV-infected population. Uveitis was initially thought to be a rare, dose-limited complication of rifabutin therapy. In an early dose-ranging tolerance study, uveitis was associated with daily doses of 1200 mg or more. Because this toxicity appeared to be dose-related, lower dosages (300–600 mg/d) of rifabutin were selected for study in subsequent clinical trials. More recent reports noting the association of uveitis with these lower dosages of rifabutin have raised concerns about the prevalence of this adverse event. In the 54 identified cases, patients presented with symptoms of unilateral or bilateral uveitis from 2 weeks to more than 7 months following initiation of rifabutin therapy. In all reported cases, patients were receiving concurrent therapy with clarithromycin and/or fluconazole, both of which have inhibitory effects on rifabutin metabolism. In most cases, uveitis resolved within 1–2 months following discontinuation of rifabutin with or without administration of topical corticosteroids. Conclusions: Rifabutin is prescribed frequently for the prophylaxis and treatment of MAC infection, especially in patients with HIV. Uveitis is a rare, dose-related toxicity of this therapy. The risk of rifabutin-associated uveitis may be increased in patients receiving concurrent therapy with clarithromycin or fluconazole because of drug interactions. Patients receiving therapy with combinations of any of these agents should be warned about signs and symptoms of uveitis and be monitored closely for the development of rifabutin toxicity. If uveitis develops, rifabutin therapy should be discontinued promptly.

Critical Review of Double-Carbapenem Therapy for the Treatment of Carbapenemase-Producing Klebsiella pneumoniae

2018 ◽  
Vol 53 (1) ◽  
pp. 70-81 ◽  
Author(s):  
Ola Mashni ◽  
Lama Nazer ◽  
Jennifer Le
Keyword(s):  
Klebsiella Pneumoniae ◽  
Clinical Studies ◽  
Case Reports ◽  
Therapeutic Option ◽  
Data Extraction ◽  
Gastrointestinal Symptoms ◽  
Current Data ◽  
Study Selection

Objective: To review the clinical data on the effectiveness and safety of double carbapenem therapy (DCT) in patients infected with carbapenemase-producing Klebsiella pneumoniae (CP-Kp). Data Sources: A literature search was performed utilizing PubMed and EMBASE (from 1966 to May 2018); bibliographies of the retrieved articles were also searched. Study Selection and Data Extraction: Articles were included if they evaluated patients with infections caused by CP-Kp and were treated with DCT. Meeting abstracts, editorials, and animal and in vitro studies were excluded. Data Synthesis: The search strategy revealed 8 case reports and 6 clinical studies (total of 171 patients) that evaluated the administration of ertapenem followed by prolonged infusions of meropenem or doripenem. Most patients were critically ill and commonly had infections in the blood, lungs, and urine. Clinical and microbiological success were reported in 70% of the patients and mortality in 24%. Adverse events, which included mostly seizures, sodium disorders, and gastrointestinal symptoms, were reported in 16 patients; none required interruption of treatment. Relevance to Patient Care and Clinical Practice: This review evaluated the clinical experience of DCT in the treatment of CP-Kp infections, based on case reports and clinical studies, for the potential role of DCT as a therapeutic option. Conclusion: Despite the limited studies, current data suggest that DCT may be an effective and safe strategy to treat CP-Kp. However, large randomized controlled trials are necessary to clearly define the role of DCT.

Sugar Paste for Treatment of Decubital Ulcers

1996 ◽  
Vol 12 (6) ◽  
pp. 289-290 ◽  
Author(s):  
Laura Tuneu Valls ◽  
Magdalena Trullás Altisen ◽  
Ramón Plá Poblador ◽  
Angels Ciurán Alvarez ◽  
Rosa Garriga Biosca
Keyword(s):  
English Language ◽  
Case Reports ◽  
Low Cost ◽  
Data Extraction ◽  
Data Synthesis ◽  
Length Of Treatment ◽  
Study Selection ◽  
Wide Variability

Objective: To review the use of sugar paste in the treatment of decubital ulcers. Data Sources: A MEDLINE, IDIS, and current journal search of English-language articles published between 1978 and 1993 on sugar paste in the treatment of ulcers. Study Selection: Case reports, cohort, epidemiologic, in vivo, and in vitro studies were evaluated. Data Extraction: Reports using granulated sugar or derivatives in the treatment of refractory cutaneous ulcers were evaluated. Data Synthesis: All the studies show that sugar paste treatment has satisfactorily resolved decubital ulcers, although a wide variability in treatment length has been seen. Considering the likely mechanisms of action for sugar paste, this wide variability may be a result of dressing frequency. In other words, for sugar paste to be most effective it has to be applied in such a way that a continuous optimal sugar concentration in the ulcer is maintained. To achieve this, dressing frequency should not be standardized, but individualized according to ulcer type, depth, and exudate, as well as patient healing capacity. Healing could probably have been achieved earlier if dressing had been individualized. Besides effectiveness and low cost, sugar paste is also safe, with few adverse events associated with its use. Conclusions: In spite of difficulties in evaluating the use of sugar paste in treatment of decubital ulcers, it has been shown to be an effective therapy for this disorder. However, we recommend that length of treatment be individualized for each patient.

Doesciprofloxacin Interact with Cyclosporine?

1994 ◽  
Vol 28 (1) ◽  
pp. 93-96 ◽  
Author(s):  
Lori L. Hoey ◽  
Kathleen D. Lake
Keyword(s):  
Drug Interaction ◽  
Case Reports ◽  
Data Extraction ◽  
Clear Correlation ◽  
Pharmacokinetic Studies ◽  
Review Of The Literature ◽  
Medline Search ◽  
Pharmacokinetic Profiles ◽  
Immune Mediated ◽  
Study Selection

OBJECTIVE: To provide the reader with a review of the literature that evaluates whether a pharmacokinetic or pharmacodynamic drug interaction exists between ciprofloxacin and cyclosporine. DATA SOURCES: A MEDLINE search was used to identify pertinent review articles, pharmacokinetic studies, and case reports. STUDY SELECTION: As both pharmacokinetic trials and case reports were few in number, all available sources were reviewed. DATA EXTRACTION: A few case reports were reviewed; however, data were extracted primarily from prospective human studies involving cyclosporine pharmacokinetic profiles. DATA SYNTHESIS: Ciprofloxacin has been reported to interact with cyclosporine during concomitant use through an interaction with the cytochrome P-450 system or by additive nephrotoxicity. Because ciprofloxacin may be used to treat a variety of infections in transplant recipients who receive cyclosporine, it is important to determine whether an interaction exists. Although cyclosporine is known to cause nephrotoxicity, only a few reports of ciprofloxacin-induced acute renal failure exist, all involving an immune-mediated interstitial nephritis. Four case reports have suggested a possible pharmacokinetic or pharmacodynamic drug interaction between cyclosporine and ciprofloxacin; however, many pharmacokinetic studies have refuted these reports. Several studies performing cyclosporine pharmacokinetic profiles have documented no increased cyclosporine concentrations, thus supporting the premise that ciprofloxacin does not interact with cyclosporine. CONCLUSIONS: Controlled studies involving cyclosporine pharmacokinetic profiles do not support a pharmacokinetic or pharmacodynamic drug interaction between ciprofloxacin and cyclosporine. Although anecdotal case reports have suggested synergistic nephrotoxicity, no clear correlation can be made. Based on our review of the literature, it can be concluded that cyclosporine and ciprofloxacin may be used together safely at the recommended dosages without increased cyclosporine monitoring.

LInezolid for the Treatment of Nocardia spp. Infections

2007 ◽  
Vol 41 (10) ◽  
pp. 1694-1699 ◽  
Author(s):  
Tomasz Z Jodlowski ◽  
Igor Melnychuk ◽  
John Conry
Keyword(s):  
Case Reports ◽  
Data Extraction ◽  
Central Nervous System Involvement ◽  
Case Series ◽  
Published Data ◽  
Data Synthesis ◽  
Study Selection ◽  
Disseminated Disease

Objective: To review the available evidence regarding the use of linezolid for the treatment of Nocardia spp. infections. Data Sources: Data were identified through a search of MEDLINE (1966-May 2007), American Search Premier (1975-May 2007), International Pharmaceutical Abstracts (1960-2007), Science Citation Index Expanded (1996-2007), and Cochrane Databases (publications archived until May 2007) using the terms linezolid and Nocardia. Study Selection and Data Extraction: Prospective and retrospective studies, case reports, case series, and in vitro studies were eligible for inclusion if they used linezolid for nocardiosis regardless of site of infection and outcome. Data Synthesis: We identified 11 published cases of linezolid use for Nocardia spp. infections. The predominant species isolated were N. asteroides (n=4; 36%) and N. farcinica (n= 3; 27%). Nocardiosis with central nervous system involvement (n= 7; 64%) or disseminated disease (n= 4; 36%) were most common. The main reason for discontinuation of previous antimicrobials was most often related to adverse effects (n= 5; 45%), followed by clinical failure (n = 3; 27%). Linezolid was associated with cure or improvement in all cases (n =11; 100%). However, the majority of patients developed serious complications that may have led to premature discontinuation of therapy with linezolid, including myelosuppression (n = 5; 45%) or possible/confirmed peripheral neuropathy (n = 2; 18%). Conclusions: The limited published data suggest that linezolid appears to be an effective alternative to trimethoprim/sulfamethoxazole for the treatment of nocardiosis. Unfortunately, the high cost and potentially serious long-term toxicities of linezolid appear to limit its use and relegate it to salvage therapy alone or in combination with other antimicrobials.

Pharmacokinetic Drug-drug Interaction of Antibiotics Used in Sepsis Care in China

2020 ◽  
Vol 21 ◽  
Author(s):  
Xuan Yu ◽  
Zixuan Chu ◽  
Jian Li ◽  
Rongrong He ◽  
Yaya Wang ◽  
...  
Keyword(s):  
Drug Interaction ◽  
Drug Interactions ◽  
Penicillin G ◽  
Literature Mining ◽  
Human Pharmacokinetics ◽  
P450 Enzyme ◽  
Drug Drug Interaction ◽  
Pharmacokinetic Drug ◽  
Sepsis Care

Background: Many antibiotics have a high potential for having an interaction with drugs, as perpetrator and/or victim, in critically ill patients, and particularly in sepsis patients. Methods: The aim of this review is to summarize the pharmacokinetic drug-drug interaction (DDI) of 45 antibiotics commonly used in sepsis care in China. Literature mining was conducted to obtain human pharmacokinetics/dispositions of the antibiotics, their interactions with drug metabolizing enzymes or transporters, and their associated clinical drug interactions. Potential DDI is indicated by a DDI index > 0.1 for inhibition or a treated-cell/untreated-cell ratio of enzyme activity being > 2 for induction. Results: The literature-mined information on human pharmacokinetics of the identified antibiotics and their potential drug interactions is summarized. Conclusion: Antibiotic-perpetrated drug interactions, involving P450 enzyme inhibition, have been reported for four lipophilic antibacterials (ciprofloxacin, erythromycin, trimethoprim, and trimethoprim-sulfamethoxazole) and three lipophilic antifungals (fluconazole, itraconazole, and voriconazole). In addition, seven hydrophilic antibacterials (ceftriaxone, cefamandole, piperacillin, penicillin G, amikacin, metronidazole, and linezolid) inhibit drug transporters in vitro. Despite no reported clinical PK drug interactions with the transporters, caution is advised in the use of these antibacterials. Eight hydrophilic antibacterials (all β-lactams; meropenem, cefotaxime, cefazolin, piperacillin, ticarcillin, penicillin G, ampicillin, and flucloxacillin), are potential victims of drug interactions due to transporter inhibition. Rifampin is reported to perpetrate drug interactions by inducing CYP3A or inhibiting OATP1B; it is also reported to be a victim of drug interactions, due to the dual inhibition of CYP3A4 and OATP1B by indinavir. In addition, three antifungals (caspofungin, itraconazole, and voriconazole) are reported to be victims of drug interactions because of P450 enzyme induction. Reports for other antibiotics acting as victims in drug interactions are scarce.

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