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where concurrent drug therapy is common in clinical practice, and they will improve product labeling and resultant use by clinicians to avoid problems.

A comprehensive DDI program was implemented in telithromycin clinical development. Telithromycin is a CYP3-PGP substrate, also a strong inhibitor to CYP3A, and a mild inhibitor to CYP2D6 (Fig. 6.35) [17]. The figure displays seven types of interactions with representative drug examples and includes the impact on C and AUC. For example, an

interaction with midazolam on CYP3A results in a 162% increase in C and 511% increase in AUC of midazolam;

max another interaction with metoprolol on CYP2D6 enzyme results in a 38% change in Cmax and a 37% change in AUC of metoprolol. Another interaction with digoxin on PGP efflux pump results in a 73% change in Cmax and a 37% change in AUC of digoxin. Telithromycin was a significant advance in antimicrobial therapy with improved spectrum of activity and less drug resistance and hence marketed, even with many DDIs.

Based on the U.S. FDA guidance, a PK study in patients with impaired renal function is recommended when renal impairment is likely to significantly alter the PK of a drug and/or its active/toxic metabolites, and a dosage adjustment is likely to be necessary for safe and effective use in such patients (Fig. 6.36). Drug clearance during hemodialysis is another important renal MPK study. Additional rationale for renal workup is a drug with narrow therapeutic index or its metabolites. The graph in this figure shows the impact on plasma levels of sotolol with varying degrees of renal function [redrawn based on the data, Ref. 20].

Full design for a renal impairment study would include eight or more subjects in each of the categories of renal impairment, and no effect would be based on the bioequivalence criteria when compared with healthy control subjects in the study. A partial design is only conducting the study with any one of the categories and may also be considered, but it would impact the drug label with limited information for clinical drug use. Subjects are considered to have normal renal function if their creatinine clearance (CLCr) values are >80 mL/min. The subjects with CLCr >50 to 80 mL/min, >30 to 50 mL/min, and < 30 mL/min are considered to have mild, moderate, and severe renal impairment, respectively. Subjects undergoing hemodialysis can also be included in the study as a separate group.

Based on the U.S. FDA guidance, a PK study in patients with impaired hepatic function is recommended if hepatic metabolism and/or excretion accounts for a substantial portion (>20% of the absorbed drug) of the elimination of a parent drug or active metabolite; if the drug and/or active metabolite is eliminated to a lesser extent (<20%) but its labeling or literature sources suggest that it is a narrow therapeutic range drug; if the metabolism of the drug is unknown and other information is lacking to suggest that hepatic elimination routes are minor (Fig. 6.37).

A full study design would be used to develop specific dosing recommendations across the entire spectrum of hepatic impairment, a study should be carried out in patients in the three Child-Pugh categories (mild, moderate, and severe), as well as healthy controls. For this study design to provide evaluable data, at least six subjects in each arm should be evaluated. A partial design may also be considered in some cases. This figure displays a concentration-time curve for ranolazine and the impact of liver disease on plasma levels at day three [21]. Moderate liver disease slows the clearance of r Objectives o Renal impairment impact on safety &

tolerability of drug o Renal impairment impact on PK of drug after single/multiple doses c Hemodialysis clearance of drug r Rationale for study o Parent or active / toxic metabolites -primarily excreted and / or metabolized via renal mechanisms c Parent or active metabolite - a narrow therapeutic index o Parent or an active metabolite - high hepatic CL vs. hepatic blood flow & significant protein binding o Impact of dialysis is of interest

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Project Management Made Easy

Project Management Made Easy

What you need to know about… Project Management Made Easy! Project management consists of more than just a large building project and can encompass small projects as well. No matter what the size of your project, you need to have some sort of project management. How you manage your project has everything to do with its outcome.

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