ISSN 2394-5125
 

Research Article 


Pharmacokinetic properties and bioequivalence of two preparations of nitisinone: an open-label, randomizedsequence, two-period, single-dose, crossover study in healthy male volunteers

Alexander L. Kulikov, Mikhail V. Pokrovskiy, Tatyana G. Pokrovskaya, Svetlana Y. Kulikova, Oleg S. Gudyrev, Alexander A. Dolzhikov, Lyudmila M. Danilenko, Olga A. Osipova, Anna A. Peresypkina.

Abstract
Background: Nitisinone - a treatment for hereditary tyrosinemia type 1, a competitive inhibitor4-
hydroxyphenyl-pyruvate dioxygenase, an enzyme of the precursor fumaryl acetoacetate hydrolase (FAH) in the
pathway of tyrosine catabolism.Objective: The purpose of this study was to study the pharmacokinetic properties
and evidence of the bioequivalence of two nitizinone preparations: recently developed capsules with a dosage of
10 mg (test) and original capsules with a dosage of 10 mg (reference) in healthy male volunteers.Methods: The
study consisted of four periods: screening, stage I (taking a test/reference preparation), the “washing” period, stage
II research (taking a test/reference preparation). The total duration of monitoring the concentration of nitisinone
in the body of the volunteer was 72 hours, which corresponds to the recommendations set forth in the regulatory
acts of the Russian Federation.Plasma drug concentrations were determined by high performance liquid
chromatography in combination with tandem mass spectrometry. The methodology was developed and validated
as part of this study. Based on the plasma concentrations of nitisinone obtained for each volunteer, the following
pharmacokinetic parameters were calculated: Tmax, AUC0-∞, AUC0-t, Cmax. Compared preparations were
considered bioequivalent if the log-transformed ratios Cmax, AUC and Cmax / AUC were within the established
range of bioequivalence from 80% to 125%. Tolerance has been evaluated by monitoring vital signs (blood
pressure, heart rate, temperature and electrocardiography), laboratoryanalysis (hematology, blood biochemistry,
liver function and urine analysis), as well as a substantive interview about adverse events.Results: Forty-two
volunteers took part and completed study (mean age [SD], 24.6 [4.50] years; weight 75.1
[6.57] kg; and height 178.8 [6.1] cm).The main pharmacokinetic parameters for the test and reference values
were: Cmax 973.44(151.14) and 986.36 (167.15) ng/ml, respectively; мedian (range) Tmax 3.0 (2.63–4.00) and
3.(3.0–5.5) h, respectively; AUC0-t, 40528.00 (7901.80) and40305.30 (7913.45) ng/ml/h, respectively;
AUC0-∞ 51887.2 (10691.29) and 51334.3 (11392.40) ng/ml/h, respectively and t1/2 21.4 (1.34) and 21.4 (1.14) h,
respectively.90% CI for the log-transformed coefficients Cmax, AUC0 - t and Cmax/AUC0 - t are from 95.73 to
102.14%, 98.58% to 103.94% and 95.16% to 101.80%, respectively(all P <0.05).All values are in the specified
range for bioequivalence. No side effects were found based on an analysis of vital signs, laboratory tests and
interviews with each volunteerConclusion: A study of the pharmacokinetics and bioequivalence of nitisinone
drugs by a randomized open cross-section method in healthy volunteers after a single oral administration allows
us to conclude that the studied drugs are bioequivalent.

Key words: nitisinone, bioequivalence, bioavailability, HPLC-MS/MS.


 
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How to Cite this Article
Pubmed Style

Alexander L. Kulikov, Mikhail V. Pokrovskiy, Tatyana G. Pokrovskaya, Svetlana Y. Kulikova, Oleg S. Gudyrev, Alexander A. Dolzhikov, Lyudmila M. Danilenko, Olga A. Osipova, Anna A. Peresypkina. Pharmacokinetic properties and bioequivalence of two preparations of nitisinone: an open-label, randomizedsequence, two-period, single-dose, crossover study in healthy male volunteers. JCR. 2020; 7(15): 112-121. doi:10.31838/jcr.07.15.16


Web Style

Alexander L. Kulikov, Mikhail V. Pokrovskiy, Tatyana G. Pokrovskaya, Svetlana Y. Kulikova, Oleg S. Gudyrev, Alexander A. Dolzhikov, Lyudmila M. Danilenko, Olga A. Osipova, Anna A. Peresypkina. Pharmacokinetic properties and bioequivalence of two preparations of nitisinone: an open-label, randomizedsequence, two-period, single-dose, crossover study in healthy male volunteers. http://www.jcreview.com/?mno=119294 [Access: September 15, 2020]. doi:10.31838/jcr.07.15.16


AMA (American Medical Association) Style

Alexander L. Kulikov, Mikhail V. Pokrovskiy, Tatyana G. Pokrovskaya, Svetlana Y. Kulikova, Oleg S. Gudyrev, Alexander A. Dolzhikov, Lyudmila M. Danilenko, Olga A. Osipova, Anna A. Peresypkina. Pharmacokinetic properties and bioequivalence of two preparations of nitisinone: an open-label, randomizedsequence, two-period, single-dose, crossover study in healthy male volunteers. JCR. 2020; 7(15): 112-121. doi:10.31838/jcr.07.15.16



Vancouver/ICMJE Style

Alexander L. Kulikov, Mikhail V. Pokrovskiy, Tatyana G. Pokrovskaya, Svetlana Y. Kulikova, Oleg S. Gudyrev, Alexander A. Dolzhikov, Lyudmila M. Danilenko, Olga A. Osipova, Anna A. Peresypkina. Pharmacokinetic properties and bioequivalence of two preparations of nitisinone: an open-label, randomizedsequence, two-period, single-dose, crossover study in healthy male volunteers. JCR. (2020), [cited September 15, 2020]; 7(15): 112-121. doi:10.31838/jcr.07.15.16



Harvard Style

Alexander L. Kulikov, Mikhail V. Pokrovskiy, Tatyana G. Pokrovskaya, Svetlana Y. Kulikova, Oleg S. Gudyrev, Alexander A. Dolzhikov, Lyudmila M. Danilenko, Olga A. Osipova, Anna A. Peresypkina (2020) Pharmacokinetic properties and bioequivalence of two preparations of nitisinone: an open-label, randomizedsequence, two-period, single-dose, crossover study in healthy male volunteers. JCR, 7 (15), 112-121. doi:10.31838/jcr.07.15.16



Turabian Style

Alexander L. Kulikov, Mikhail V. Pokrovskiy, Tatyana G. Pokrovskaya, Svetlana Y. Kulikova, Oleg S. Gudyrev, Alexander A. Dolzhikov, Lyudmila M. Danilenko, Olga A. Osipova, Anna A. Peresypkina. 2020. Pharmacokinetic properties and bioequivalence of two preparations of nitisinone: an open-label, randomizedsequence, two-period, single-dose, crossover study in healthy male volunteers. Journal of Critical Reviews, 7 (15), 112-121. doi:10.31838/jcr.07.15.16



Chicago Style

Alexander L. Kulikov, Mikhail V. Pokrovskiy, Tatyana G. Pokrovskaya, Svetlana Y. Kulikova, Oleg S. Gudyrev, Alexander A. Dolzhikov, Lyudmila M. Danilenko, Olga A. Osipova, Anna A. Peresypkina. "Pharmacokinetic properties and bioequivalence of two preparations of nitisinone: an open-label, randomizedsequence, two-period, single-dose, crossover study in healthy male volunteers." Journal of Critical Reviews 7 (2020), 112-121. doi:10.31838/jcr.07.15.16



MLA (The Modern Language Association) Style

Alexander L. Kulikov, Mikhail V. Pokrovskiy, Tatyana G. Pokrovskaya, Svetlana Y. Kulikova, Oleg S. Gudyrev, Alexander A. Dolzhikov, Lyudmila M. Danilenko, Olga A. Osipova, Anna A. Peresypkina. "Pharmacokinetic properties and bioequivalence of two preparations of nitisinone: an open-label, randomizedsequence, two-period, single-dose, crossover study in healthy male volunteers." Journal of Critical Reviews 7.15 (2020), 112-121. Print. doi:10.31838/jcr.07.15.16



APA (American Psychological Association) Style

Alexander L. Kulikov, Mikhail V. Pokrovskiy, Tatyana G. Pokrovskaya, Svetlana Y. Kulikova, Oleg S. Gudyrev, Alexander A. Dolzhikov, Lyudmila M. Danilenko, Olga A. Osipova, Anna A. Peresypkina (2020) Pharmacokinetic properties and bioequivalence of two preparations of nitisinone: an open-label, randomizedsequence, two-period, single-dose, crossover study in healthy male volunteers. Journal of Critical Reviews, 7 (15), 112-121. doi:10.31838/jcr.07.15.16