LAUSR

A new drug application (NDA) for a systemically active, new therapeutic entity (NTE) may contain clinical studies that administered a small molecule or a biologic only by the intended route. This may be self-evident for NTEs given intravenously, but less so for NTEs whose intended route of administration is not intravenous. Because the US Food and Drug Administration (FDA) accepts apparent pharmacokinetic (PK) parameters of NTEs determined after nonintravenous administration, sponsors decide whether studies with additional intravenous treatment arms are included in the development plan of an NTE, and thus, whether the true PK parameters, clearance, (CL), volume of distribution, (Vd), and derived parameters such as nonrenal clearance (CLnr), terminal elimination phase half-life (t1/2z), and absolute bioavailability (F) of NTEs will or will not be known. Detailed information on methods and results of the PK studies performed by sponsors are submitted as part of theNDA.After approval of anNTE, information on the PK parameters is provided in the publicly available Clinical Pharmacology reviews of the NDAs. Sponsors of NTEs may also publish results of PK studies in the scientific literature. The goals of this commentary are to investigate how many recently approved NTEs intended for nonintravenous administration performed additional PK studies with intravenous drug administration and to discuss the implications of the findings. A newer method is highlighted that facilitates obtaining information on the PK of drugs after intravenous administration. The Clinical Pharmacology reviews of the NDA submissions available from the FDA website (Drugs@FDA) were screened for PK studies with intravenous drug administration. Small molecules were selected for this review because they represent the largest group among the newly and previously approved NTEs. Additionally, PubMed sources using key words such as “absolute bioavailability,” “pharmacokinetics,” “micro-dose,” and “tracer kinetics” were employed. As shown in Table 1, only 31 (39%) of the 80 NDA submissions of small molecules with systemic activity intended exclusively for oral administration and approved by the FDA during the 5-year period between 2013 and 2017 contained information on at least 1 of the 5 PK parameters that can be obtained only after intravenous administration. For 22 of the 31 small-molecule NTEs, information on the true PK parameters was reported also in the indexed biomedical literature.1–22 The PK of all 31 drugs is reportedly dose proportional. For the large majority of the small-molecule NTEs, information on the true parameters was obtained from absolute bioavailability studies in which the NTE is administered by the intended route and the intravenous route that serves as the 100% bioavailable control. The information provided by the NDAs and the published literature for the 31 small-molecule NTEs that conducted studies with intravenous drug administration suggests that unlabeled drug, drug labeled with a nonstable isotope (14C), and drug labeled with stable isotopes (13C or 13C/15N) was used for 18, 10, and 3, respectively. The labeled drug moieties were administered intravenously in micro-doses in 13 absolute bioavailability studies that used a newer design described below in more detail.