Study of the pharmacokinetics of various drugs under conditions of antiorthostatic hypokinesia and the pharmacokinetics of acetaminophen under long-term spaceflight conditions

Abstract

Objectives To study the pharmacokinetics and relative bioavailability of drugs of different chemical structure and pharmacological action under conditions simulating the effects of some factors of spaceflight, as well as the peculiarities of the pharmacokinetics of acetaminophen under long-term spaceflight conditions. Methods The pharmacokinetics of verapamil (n=8), propranolol (n=8), etacizine (n=9), furosemide (n=6), and acetaminophen (n=7) in healthy volunteers after a single oral administration under normal conditions (background) and under antiorthostatic hypokinesia (ANOH), the pharmacokinetics of acetaminophen in spaceflight members under normal ground conditions (background) (n=8) and under prolonged spaceflight conditions (SF) (n=5) were studied. Results The stay of volunteers under antiorthostatic hypokinesia had different effects on the pharmacokinetics and bioavailability of drugs: Compared to background, there was a decreasing trend in Vz for verapamil (−54 Δ%), furosemide (−20 Δ%), propranolol (−8 Δ%), and acetaminophen (−9 Δ%), but a statistically significant increase in Vz was found for etacizine (+39 Δ%); there was an increasing trend in Clt for propranolol (+13 Δ%) and acetaminophen (+16 Δ%), and a decreasing trend in Clt for etacizine, verapamil, and furosemide (−22, −23 and −9 Δ% respectively) in ANOH. The relative bioavailability of etacizine, verapamil, and furosemide in ANOH increased compared to background (+40, +23 and +13 Δ%, respectively), propranolol and acetaminophen decreased (−5 and −12 Δ% accordingly). The relative rate of absorption of etacizine and furosemide in ANOH decreased (−19 and −20 Δ%, respectively) while that of verapamil, propranolol, and acetaminophen increased (+42, +58 and +26 Δ%, respectively). A statistically significant decrease in AUC0-∞ (−57 Δ%), Cmax (−53 Δ%), relative bioavailability of acetaminophen (−52 Δ%) and a sharp increase in Clt (+147 Δ%), Tmax (+131 Δ%) as well as a trend towards a significant decrease in T1/2 (−53 Δ%), MRT (−36 Δ%) and a moderate increase in Vz (+24 Δ%) were found under control compared to background. Unidirectional changes in AUC0-∞, Clt, T1/2, MRT and relative bioavailability of acetaminophen, which are more pronounced in SF and opposite dynamics for Cmax, Tmax, Vz were found in ANOH and SP compared to background studies. Conclusions The data obtained allow recommending the studied drugs for rational pharmacotherapy in the possible development of cardiovascular disease in manned spaceflight.

Physiological adaptations affecting drug pharmacokinetics in space: what do we really know? A critical review of the literature

“…Based on these results, the authors concluded that encapsulated acetaminophen was preferred to the tablet form in space. A recent report largely confirmed the PK data obtained on the ISS, using the tablet formulation of acetaminophen (Kovachevich et al, 2009), in longer duration spaceflight (127–414 days) (Polyakov et al, 2021). This study was carried out applying a similar protocol, using saliva samples and included data from crewmembers that participated in space missions to the MIR orbital station.…”

“…These data therefore suggest that the rate of drug absorption is increased during 6° HDT BR, in contrast to that observed using the HBR (Renwick et al, 1992; Rumble et al, 1991). The PK of acetaminophen was recently studied in a group of seven male subjects exposed to 2 days of 8° HDT BR (Polyakov et al, 2021). The study showed relevant differences in the profile of the averaged PK curves for acetaminophen among normal motion conditions (background) and 8° HDT BR.…”

“…The latter is consistent with data obtained during long-term spaceflight, although the magnitude of the reduction in drug bioavailability was larger in space than in subjects exposed to short-term HDT BR. However, as mentioned above, different cohorts of subjects and different specimens were used to assess acetaminophen PK in these two settings thus precluding solid conclusions (Polyakov et al, 2021).…”

“…Since then, only two original articles on drug PK in human spaceflights have appeared in the literature. The most commonly used experimental model of microgravity for PK studies is the BR model, either in the horizontal position (HBR), that is, six articles published between years 1976 and 1992, or the head‐down tilt (HDT) BR, that is, six articles published between years 1995 and 2011 and one publication in 2021 (Polyakov et al, 2021). Despite the number of review articles on drug PK in space available in the literature, this is the first time that a critical approach has been undertaken in presenting these data.…”

“…Despite the number of review articles on drug PK in space available in the literature, this is the first time that a critical approach has been undertaken in presenting these data. By estimating the number and type of publications in the field over time, our analysis, which also includes the most recent in‐flight data on drug PK (Polyakov et al, 2021), directly shows a paucity of original results on drug PK in space and a lack of consistency among different studies on the same drug. In addition, we sought to analyse the reasons behind this evidence and provide means to facilitate drug PK studies in space.…”