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Drug accumulation ratio

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In pharmacokinetics, the drug accumulation ratio (Rac) is the ratio of accumulation of a drug under steady state conditions (i.e., after repeated administration) as compared to a single dose. The higher the value, the more the drug accumulates in the body. An Rac of 1 means no accumulation.

Studies

The accumulation ratio of a specific drug in humans is determined by clinical studies. According to a 2013 analysis, such studies are typically done with 10 to 20 subjects who are given one single dose followed by a washout phase of seven days (median), and then seven to 14 repeated doses to reach steady state conditions. Blood samples are drawn 11 times (median) per subject to determine the blood concentration of the studied drug.

Calculation

The drug accumulation ratio, according to one common definition, is the ratio of the green area to the blue area.

There are various competing calculation methods for the drug accumulation ratio, yielding somewhat different results. A commonly used formula defines Rac as the ratio of the area under the curve (AUC) during a single dosing interval under steady state conditions to the AUC during a dosing interval after one single dose:

R a c = AUC ⁡ ( τ , s s ) AUC ⁡ ( τ , 1 ) {\displaystyle R_{ac}={\frac {\operatorname {AUC} (\tau ,ss)}{\operatorname {AUC} (\tau ,1)}}}

where τ {\displaystyle \tau } is the dosing interval, ss means steady state and 1 stands for a single-dose application.

Another definition sets Rac to the ratio of the average drug concentration during one day under steady state conditions to the concentration after a single dose.

Examples

Drug Trade name Rac Reference
Dabrafenib Tafinlar 0.73
Rosuvastatin Crestor 1.37 in hemodialysis patients
Lisinopril Prinivil and others 1.38
Ivacaftor Kalydeco 2.2–2.9
Trametinib Mekinist 6.0 at 2 mg once daily

References

  1. ^ Li, Lujin; Li, Xianxing; Xu, Ling; Sheng, Yucheng; Huang, Jihan; Zheng, Qingshan (2013). "Systematic Evaluation of Dose Accumulation Studies in Clinical Pharmacokinetics". Current Drug Metabolism. 14 (5): 605–615. doi:10.2174/13892002113149990002. PMID 23701162.
  2. Swartz, Conrad M. (1997). "A Simplified Account of Drug Accumulation and Steady-State Dose Equivalences". The Journal of Clinical Pharmacology. 37 (10): 962–970. doi:10.1002/j.1552-4604.1997.tb04271.x. PMID 9505988.
  3. "Tafinlar: EPAR – Product Information" (PDF). European Medicines Agency. 1 February 2021.
  4. Birmingham, B. K.; Swan, S. K.; Puchalski, T.; Mitchell, P.; Azumaya, C.; Zalikowski, J.; Wang, Y. (2013). "Pharmacokinetic and pharmacodynamic profile of rosuvastatin in patients with end-stage renal disease on chronic haemodialysis". Clinical Drug Investigation. 33 (4): 233–241. doi:10.1007/s40261-013-0071-3. PMID 23494963.
  5. Beermann, B.; Till, A. E.; Gomez, H. J.; Hichens, M.; Bolognese, J. A.; Junggren, I. (1989). "Pharmacokinetics of lisinopril (IV/PO) in healthy volunteers". Biopharmaceutics & Drug Disposition. 10 (4): 397–409. doi:10.1002/bdd.2510100407. PMID 2547465.
  6. "Kalydeco: EPAR – Product Information" (PDF). European Medicines Agency. 12 May 2021.
  7. "Mekinist: EPAR – Product Information" (PDF). European Medicines Agency. 26 February 2021.
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