A Systematic Review and Meta-Analysis Reveals Altered Drug Pharmacokinetics in Humans During Acute Exposure to Terrestrial High Altitude-Clinical Justification for Dose Adjustment?

Bailey, Damian Miles, Benjamin S. Stacey, and Mark Gumbleton. A systematic review and meta-analysis reveals altered drug pharmacokinetics in humans during acute exposure to terrestrial high altitude-clinical justification for dose adjustment? High Alt Med Biol. 19:141-148, 2018.

OBJECTIVE: While physiological responses during acute ascent to terrestrial high altitude (HA) have the potential to alter the pharmacokinetics (PKs) that define absorption and disposition of medicinal drugs, there have been no systematic reviews and meta-analyses performed to date.

METHODS: We conducted a systematic literature search in June 2017 using NCBI PubMed, EMBASE, Web of Science, and Ovid MEDLINE databases to identify relevant observational studies. Studies were deemed eligible based on the following criteria: (1) participants: healthy, nonacclimatized male or female lowlanders (born and bred at sea level) and (2) environment: exposure to low altitude (LA, ≤600 m), followed by terrestrial high altitude (HA, ≤24 hours to ≥2500 m), the time course specifically selected to avoid interpretive complications associated with erythrocytosis. All PK parameters were standardized to be in the same units and the weighted standardized mean difference (SMD) calculated using a combination of fixed and random effects models with heterogeneity evaluated using χ2 and I2 statistics.

RESULTS: Of 20,840 studies reviewed, 6 prospective cohort studies (n = 75) qualified for inclusion, with participants exposed to a mean altitude of 4025 (mean) ± 380 (SD) m. We observed increases for absorption half-life (SMD: 0.40, 95% CI: 0.01-0.80, p = 0.04], elimination half-life (SMD: 0.89, 95% CI: 0.30-1.48, p = 0.003), and erythrocyte binding (SMD: 0.52, 95% CI: 0.16-0.88, p = 0.004) and reduction in clearance (SMD: -0.56, 95% CI: -1.13 to 0.00, p = 0.05).

CONCLUSIONS: Collectively, these findings reveal impairments in both oral absorption and corresponding clearance of the, although limited, sample of drugs at HA that may potentially require closer patient monitoring and dose adjustments to maintain therapeutic efficacy and avoid incidental toxicity.