Cyclophosphamide and 4‐hydroxycyclophosphamide pharmacokinetics in patients with glomerulonephritis secondary to lupus and small vessel vasculitis

• Published in: British journal of clinical pharmacology Vol. 74; no. 3; pp. 445 - 455
• Main Authors: Joy, Melanie S., La, Mary, Wang, Jinzhao, Bridges, Arlene S., Hu, Yichun, Hogan, Susan L., Frye, Reginald F., Blaisdell, Joyce, Goldstein, Joyce A., Dooley, Mary Anne, Brouwer, Kim L. R., Falk, Ronald J.
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01.09.2012; Blackwell; Blackwell Science Inc
• Subjects: 4‐hydroxycylophosphamide; Adult; Aged; Area Under Curve; Aryl Hydrocarbon Hydroxylases - genetics; ATP Binding Cassette Transporter, Sub-Family B; ATP-Binding Cassette, Sub-Family B, Member 1 - genetics; Biological and medical sciences; Chromatography, Liquid; cyclophosphamide; Cyclophosphamide - analogs & derivatives; Cyclophosphamide - pharmacokinetics; Cytochrome P-450 CYP2B6; Female; Glomerulonephritis; Glomerulonephritis - etiology; Glomerulonephritis - physiopathology; Half-Life; Humans; Kidneys; Lupus Erythematosus, Systemic - complications; lupus nephritis; Male; Mass Spectrometry; Medical sciences; Middle Aged; Nephrology. Urinary tract diseases; Nephropathies. Renovascular diseases. Renal failure; Oxidoreductases, N-Demethylating - genetics; pharmacogenomics; Pharmacokinetics; Pharmacology. Drug treatments; Polymorphism, Single Nucleotide; Sarcoidosis. Granulomatous diseases of unproved etiology. Connective tissue diseases. Elastic tissue diseases. Vasculitis; Serum Albumin - metabolism; Urinary system involvement in other diseases. Miscellaneous; Vasculitis - complications; Antineoplastic agent; Glomerulonephritis; Skin disease; Genomics; Autoimmune disease; Cardiovascular disease; Lupus nephritis; Vascular disease; Systemic lupus erythematosus; Vasculitis; Blood vessel; Systemic disease; Genetics; Pharmacogenomics; Kidney disease; Human; Immunopathology; Connective tissue disease; Secondary; Urinary system disease; Alkylating agent; Oxazaphosphinane derivatives; Cyclophosphamide; Nitrogen mustard; Circulatory system; 4-hydroxycylophosphamide; Pharmacokinetics
• ISSN: 0306-5251; 1365-2125; 1365-2125
• DOI: 10.1111/j.1365-2125.2012.04223.x

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • The pharmacokinetics of cyclophosphamide and 4‐hydroxycyclophosphamide in cancer patients have been well described. The current study was conducted to document the pharmacokinetics of cyclophosphamide and 4‐hydroxycyclophosphamide in patients with glomerulonephritis. The study was necessary due to the numerous clinical abnormalities that are present in glomerulonephritis (altered glomerular filtration rate, proteinuria, hypoalbuminaemia) which can alter the disposition of drugs. WHAT THIS STUDY ADDS • This study documents the differences in pharmacokinetics of cyclophosphamide and 4‐hydroxycyclophosphamide in glomerulonephritis vs. the cancer population. The current results demonstrate that clinical and pharmacogenetic covariates can both alter the disposition of cyclophosphamide and 4‐hydroxycyclophosphamide in glomerulonephritis. AIMS Cyclophosphamide, the precursor to the active 4‐hydroxycyclophosphamide, is used in active glomerulonephritis despite limited pharmacokinetics data. The pharmacokinetics of cyclophosphamide and 4‐hydroxycyclophosphamide were evaluated. The influence of laboratory and pharmacogenomic covariates on pharmacokinetics was evaluated as a secondary aim. METHODS Glomerulonephritis patients (n = 23) participated in a pharmacokinetic evaluation. Blood was serially collected and assayed for cyclophosphamide and 4‐hydroxycyclophosphamide by LC/MS methods. Kidney function, serum albumin and polymorphisms in drug metabolism or transport genes were evaluated. Analyses included non‐compartmental pharmacokinetics and parametric and non‐parametric statistics. RESULTS The mean area under the plasma concentration–time curve (AUC(0,∞)) data were 110 100 ± 42 900 ng ml−1 h and 5388 ± 2841 ng ml−1 h for cyclophosphamide and 4‐hydroxycyclophosphamide, respectively. The mean metabolic ratio was 0.06 ± 0.04. A statistically significant relationship was found between increased serum albumin and increased half‐life (0.584, P = 0.007, 95% CI 0.176, 0.820) and a borderline relationship with AUC(0,∞) (0.402, P = 0.079, 95% CI –0.064, 0.724) for 4‐hydroxycyclophosphamide. Covariate relationships that trended toward significance for cyclophosphamide included decreased serum albumin and increased elimination rate constant (–0.427, P = 0.061, 95% CI 0.738, 0.034), increased urinary protein excretion and increased AUC(0,∞) (–0.392, P = 0.064, 95% CI –0.699 to 0.037), decreased Cmax (0.367, P = 0.085, 95% CI –0.067, 0.684) and decreased plasma clearance (–0.392, P = 0.064, 95% CI –0.699, 0.037). CYP2B6*9 variants vs. wildtype were found to have decreased elimination rate constant (P = 0.0005, 95% CI 0.033, 0.103), increased Vd (P = 0.0271, 95% CI −57.5, −4.2) and decreased Cmax (P = 0.0176, 95% CI 0.696, 6179) for cyclophosphamide. ABCB1 C3435T variants had a borderline decrease in cyclophosphamide elimination rate constant (P = 0.0858; 95% CI –0.005, 0.102). CONCLUSIONS Pharmacokinetics of cyclophosphamide and 4‐hydroxycyclophosphamide in patients with lupus nephritis and small vessel vasculitis are similar. Clinical and pharmacogenetic covariates alter disposition of cyclophosphamide and 4‐hydroxycyclophosphamide. Clinical findings of worsened glomerulonephritis lead to increased exposure to cyclophosphamide vs. the active 4‐hydroxycyclophosphamide, which could have relevance in terms of clinical efficacy. The CYP2B6*9 and ABCB1 C3435T polymorphisms alter the pharmacokinetics of cyclophosphamide and 4‐hydroxycyclophosphamide in glomerulonephritis.