Stable Isotope Techniques in Early Drug Development: An Economic Evaluation

Browne, Thomas R.

doi:10.1002/j.1552-4604.1998.tb04418.x

Cited by 14 publications

(12 citation statements)

References 24 publications

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“…Secondly, the motivation to prepare deuterated drugs to study how the undeuterated drug or related compounds act in the body is discussed. This is supported by references such as Baillie [76], Browne [77], Cherrah et al [78], Gouyette [79], Haskins [80], Pieniaszek et al [81], Tonn et al [82] or Wolen [83]. …”

Section: Current State Of 35 Usc §103 Rejectionsmentioning

confidence: 59%

Deuterated drugs: where are we now?

Timmins

2014

Expert Opinion on Therapeutic Patents

149

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Introduction Deuterated versions of existing drugs can exhibit improved pharmacokinetic or toxicological properties due the stronger deuterium-carbon bond modifying their metabolism. There is great interest in the current state of development of this approach. Areas Covered This review covers recent US patent applications and prosecutions in this area, that are based upon beneficial modifications in metabolism of deuterated versions of existing drugs. The current state of 35 U.S.C. §103 ‘obviousness’ rejections, are emphasized as is the development of strategies to overcome such rejections. Current trials and market considerations are also discussed. Expert Opinion Deuterated drugs collectively are worth at least a billion dollars. It would seem that the likelihood of obviousness rejections is increasing in this area. However, careful elucidation of metabolic outcomes from deuteration that would not be anticipated from the prior art, and are instead unexpected and unobvious, has enabled allowance. Showing drug deuteration alters pharmacokinetics by mechanisms not currently part of the prior art surrounding, deuterated drugs has also been successful. Development of these and other strategies, combined with developing the extensive base of issued patents will enable the field to remain commercially attractive for some time.

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Section: Current State Of 35 Usc §103 Rejectionsmentioning

confidence: 59%

Deuterated drugs: where are we now?

Timmins

2014

Expert Opinion on Therapeutic Patents

149

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“…29,30 The use of a micro-dose administered intravenously has 3 advantages. A micro-dose is defined as 1/100th of a pharmacologically active dose or ࣘ100 μg, whichever is smaller.…”

Section: Traditional and Alternative Designs Of Studies With Intravenmentioning

confidence: 99%

“…29,30 Labeling drugs with 13 C, 14 C, or 15 N minimizes the potential for an isotope effect because the relative increase in neutrons of the labeled relative to the unlabeled moiety is small. The drug may exhibit low solubility or may be irritating, necessitating the development of a suitable and stable intravenous dosage form.…”

Section: Traditional and Alternative Designs Of Studies With Intravenmentioning

confidence: 99%

Why Collecting Pharmacokinetic Information After Intravenous Drug Administration Is Important

Hinderling¹,

Papoian²

2020

Clinical Pharm in Drug Dev

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Keywords absolute bioavailability, alternative study design, intravenous drug administration, micro-dose, model predictions, true PK parameters 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 (t 1/2z ), 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 the NDA. After approval of an NTE, 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. 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 ...

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“…To improve the reliability of metabolite identification by full‐scan MS, stable isotopic labeling ( 2 H, 13 C, 15 N, 18 O, 34 S) has been used 77–80. The use of stable isotope‐labeled drugs allows safe experiments with humans, which provides great advantages over the use of radiolabels.…”

Section: Detection Of Metabolites and Determination Of The Site Of Bimentioning

confidence: 99%

Liquid chromatography/atmospheric pressure ionization–mass spectrometry in drug metabolism studies

et al. 2003

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The study of the metabolic fate of drugs is an essential and important part of the drug development process. The analysis of metabolites is a challenging task and several different analytical methods have been used in these studies. However, after the introduction of the atmospheric pressure ionization (API) technique, electrospray and atmospheric pressure chemical ionization, liquid chromatography/mass spectrometry (LC/MS) has become an important and widely used method in the analysis of metabolites owing to its superior specificity, sensitivity and efficiency. In this paper the feasibility of LC/API-MS techniques in the identification, structure characterization and quantitation of drug metabolites is reviewed. Sample preparation, LC techniques, isotope labeling, suitability of different MS techniques, such as tandem mass spectrometry, and high-resolution MS in drug metabolite analysis, are summarized and discussed. Automation of data acquisition and interpretation, special techniques and possible future trends are also the topics of the review.

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Stable Isotope Techniques in Early Drug Development: An Economic Evaluation

Cited by 14 publications

References 24 publications

Deuterated drugs: where are we now?

Deuterated drugs: where are we now?

Why Collecting Pharmacokinetic Information After Intravenous Drug Administration Is Important

Liquid chromatography/atmospheric pressure ionization–mass spectrometry in drug metabolism studies

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