Flip-flop Pharmacokinetics – Delivering a Reversal of Disposition: Challenges and Opportunities During Drug Development

Abstract

Flip-flop pharmacokinetics is a phenomenon often encountered with extravascularly administered drugs. Occurrence of flip-flop spans preclinical to human studies. The purpose of this article is to analyze both the pharmacokinetic interpretation errors and opportunities underlying the presence of flip-flop pharmacokinetics during drug development. Flip-flop occurs when the rate of absorption is slower than the rate of elimination. If it is not recognized, it can create difficulties in the acquisition and interpretation of pharmacokinetic parameters. When flip-flop is expected or discovered, a longer duration of sampling may be necessary in order to avoid overestimation of fraction of dose absorbed. Common culprits of flip-flop disposition are modified dosage formulations; however, formulation characteristics such as the drug chemical entities themselves or the incorporated excipients can also cause the phenomenon. Yet another contributing factor is the physiological makeup of the extravascular site of administration. In this article, these causes of flip-flop pharmacokinetics are discussed with incorporation of relevant examples and the implications for drug development outlined.

An integrated pharmacokinetic and pharmacodynamic study of a new drug of abuse, methylone, a synthetic cathinone sold as “bath salts”

“…administration, suggesting a pharmacokinetic flip-flop model. Flipflop pharmacokinetics is a phenomenon often encountered with extravascular administered drugs (Yáñez et al, 2011). Flip-flop occurs when the rate of absorption is slower than the rate of elimination.…”

Pharmacokinetics, Safety, and Tolerability of Single-Dose Intravenous (ZTI-01) and Oral Fosfomycin in Healthy Volunteers

“…In this study, the k a for oral fosfomycin was 0.0175 h Ϫ1 , while the k e was 0.1093 h Ϫ1 , indicating a slow first-order absorption process. This phenomenon, sometimes known as flip-flop kinetics (27,28), has been reported with other antimicrobials and may be a result of the saturable carrier-mediated phosphate transport system and nonsaturable first-order absorption processes of fosfomycin in the small intestine (29). All subjects in this study were fasted and free from concomitant medications at the time of study drug administration, therefore factors affecting absorption of oral fosfomycin tromethamine deserve further exploration.…”

Assessment of Intestinal Availability (FG) of Substrate Drugs of Cytochrome P450s by Analyzing Changes in Pharmacokinetic Properties Caused by Drug–Drug Interactions

“…For the selection of clinical studies, the following criteria were applied: 1) to avoid erroneous estimation of t 1/2 , studies with second peaks after the time taken to reach the maximum concentration in the presence of inhibitors and studies with insufficient observation periods for estimation of t 1/2 were excluded; and 2) to avoid flip-flop, conditions by Garrett et al were applied considering the absorption rate constant, the elimination rate constant, and intravenous data (Garrett, 1994;Yáñez et al, 2011). When multiple studies were available for one substrate, F G was assessed as the mean of F G values calculated for each drug.…”