Drug-drug in­ter­ac­tions: FDA is­sues guid­ance on clin­i­cal, in vit­ro stud­ies

The FDA on Thurs­day fi­nal­ized two guid­ances pro­vid­ing rec­om­men­da­tions to drug­mak­ers on eval­u­at­ing po­ten­tial drug-drug in­ter­ac­tions (DDIs) for new drugs through clin­i­cal and in vit­ro test­ing.

“To­geth­er, the two fi­nal guid­ances de­scribe a sys­tem­at­ic risk-based ap­proach to eval­u­a­tion and com­mu­ni­ca­tion of DDIs,” the FDA writes.

The two guid­ances fi­nal­ize draft ver­sions re­leased in 2017 and have been re­vised to clar­i­fy their scope, pro­vide ad­di­tion­al con­sid­er­a­tions for con­duct­ing prospec­tive stud­ies and to ex­plain “when DDI stud­ies are need­ed for drugs iden­ti­fied as trans­porter sub­strates from in vit­ro stud­ies.” Both guid­ances have been re­named from their draft ver­sions to re­flect an em­pha­sis on in­ves­ti­gat­ing the cy­tochrome P450 (CYP) en­zyme and trans­porter-me­di­at­ed drug in­ter­ac­tions.

The FDA ex­plains that DDIs are a crit­i­cal fac­tor in a drug’s over­all ben­e­fit-risk pro­file and stress­es that clin­i­cal­ly rel­e­vant DDIs should be iden­ti­fied dur­ing drug de­vel­op­ment, known at the time of ap­proval, in­clud­ed in la­bel­ing and mon­i­tored on an on­go­ing ba­sis.

“The con­comi­tant use of more than one med­ica­tion in a pa­tient is com­mon. Unan­tic­i­pat­ed, un­rec­og­nized, or mis­man­aged DDIs are an im­por­tant cause of mor­bid­i­ty and mor­tal­i­ty as­so­ci­at­ed with pre­scrip­tion drug use and have oc­ca­sion­al­ly been the ba­sis for with­draw­al of ap­proved drugs from the mar­ket. In some in­stances, un­der­stand­ing how to safe­ly man­age a DDI can al­low ap­proval of a drug that would oth­er­wise have an un­ac­cept­able lev­el of risk,” the FDA writes.

In Vit­ro Drug In­ter­ac­tion Stud­ies

The FDA’s 43-page guid­ance on in vit­ro drug in­ter­ac­tion stud­ies dis­cuss­es ap­proach­es to eval­u­ate the DDI po­ten­tial of in­ves­ti­ga­tion­al drugs and how those stud­ies can in­form clin­i­cal DDI stud­ies down the road.

The guid­ance ex­plains that “eval­u­at­ing the DDI po­ten­tial of an in­ves­ti­ga­tion­al new drug in­volves iden­ti­fy­ing the prin­ci­pal routes of the drug’s elim­i­na­tion; es­ti­mat­ing the con­tri­bu­tion of en­zymes and trans­porters to the drug’s dis­po­si­tion; and char­ac­ter­iz­ing the ef­fect of the drug on en­zymes and trans­porters.”

The re­sults of in vit­ro DDI stud­ies and phar­ma­co­ki­net­ic (PK) da­ta “pro­vide mech­a­nis­tic in­for­ma­tion that can in­form the need for and prop­er de­sign of po­ten­tial fu­ture clin­i­cal stud­ies.”

The guid­ance goes on to dis­cuss ap­proach­es to eval­u­at­ing me­tab­o­lism-me­di­at­ed and trans­porter-me­di­at­ed drug in­ter­ac­tions, as well as ap­proach­es to eval­u­ate the DDI po­ten­tial of metabo­lites.

Clin­i­cal Drug In­ter­ac­tion Stud­ies

In the 24-page fi­nal guid­ance on clin­i­cal drug in­ter­ac­tion stud­ies, the FDA ex­plains when DDI stud­ies should be con­duct­ed and pro­vides rec­om­men­da­tions for the de­sign, con­duct and in­ter­pre­ta­tion of those stud­ies.

Specif­i­cal­ly, the guid­ance dis­cuss­es dif­fer­ent DDI study de­signs and con­sid­er­a­tions for prospec­tive DDI stud­ies, CYP-me­di­at­ed in­ter­ac­tions, trans­porter-me­di­at­ed re­ac­tions and cock­tail study ap­proach­es. The guid­ance al­so dis­cuss­es oth­er fac­tors that could im­pact drug in­ter­ac­tions, such as pa­tient ge­net­ics, smok­ing and com­plex drug in­ter­ac­tions.

Ad­di­tion­al­ly, the guid­ance pro­vides rec­om­men­da­tions on what DDI in­for­ma­tion should be in­clud­ed in la­bel­ing and refers spon­sors to four oth­er rel­e­vant la­bel­ing guid­ances.

Fed­er­al Reg­is­ter No­tice

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