Pharmacokinetics of Cyclophosphamide in Scleroderma Treated By Cyclophosphamide Versus Transplantation

David Adams¹, Keith Sullivan², Ivan Spasojevic¹, Ping Fan¹, Mario Sampson³, Michael Cohen-Wolkowiez³, E. William St Clair⁴, Rob Woolson⁵, Jan Storek⁶, Mary Ellen Csuka⁷, Ashley Pinckney⁵, Beverly Welch⁸, Ellen Goldmuntz⁹, Daniel E. Furst¹⁰, Leslie Crofford¹¹, Lynette Keyes-Elstein¹², Maureen Mayes¹³, Peter McSweeney¹⁴ and Richard Nash¹⁴, ¹Medicine, Duke University Medical Center, Durham, NC, ²Duke University Medical Center, Durham, NC, ³Pediatrics-Infectious Disease, Duke University Medical Center, Durham, NC, ⁴Rheumatology, Duke University Medical Center, Durham, NC, ⁵Rho Federal Systems, Inc., Chapel Hill, NC, ⁶University of Calgary, Calgary, AB, Canada, ⁷Medicine, Medical College of Wisconsin, Milwaukee, WI, ⁸National Institutes of Health, Bethesda, MD, ⁹NIAID, NIH, Bethesda, MD, ¹⁰University of Washington, Seattle, WA, ¹¹Division of Rheumatology and Immunology, Vanderbilt University Medical Center, Nashville, TN, ¹²Clinical Statistics, Rho Federal Systems, Inc., Chapel Hill, NC, ¹³Rheumatology, University of Texas at Houston, Houston, TX, ¹⁴Colorado Blood Cancer Institute, Denver, CO

Meeting: 2018 ACR/ARHP Annual Meeting

Keywords: cyclophosphamide, pharmacokinetics, scleroderma and transplantation

Session Information

Date: Monday, October 22, 2018

Title: Systemic Sclerosis and Related Disorders – Clinical Poster II

Session Type: ACR Poster Session B

Session Time: 9:00AM-11:00AM

Background/Purpose:

The pharmacokinetics (PK) of cyclophosphamide (CP) and its primary active metabolite, 4-hydroxycyclophosphamide (4-OH-CP) have not been adequately studied in scleroderma. The hypothesis of this sub-study of the Scleroderma: Cyclophosphamide or Transplantation (SCOT) trial (Sullivan, KM et al., N Engl J Med 2018;378:35-47) was that response to CP, defined as event-free survival (EFS) at 54 months, will correlate with exposure (CxT) to the active metabolite 4-OH-CP. Secondary objectives were to determine whether the initial CP exposure enhances activation of a second dose (auto-activation) and to evaluate the effect of CP on myelosuppression.

Methods:

CP was infused over 1 to 2 hours in both study arms. Subjects in the transplant arm received a conditioning regimen of 120 mg/kg (mean 2099 mg/m²). Subjects in the CP arm received an initial infusion of 500 mg/m², then twelve doses of 750 mg/m²; PK analyses were only done after the first two doses . For transplant, 3 ml blood samples were drawn pre-dose and at 2, 4, 6, 8, 10, and 23 hours after infusion. For the CP arm, samples were collected at pre-dose, 0.5, 1, 2, and 24 hours. All samples were immediately derivatized with O-(2,3,4,5,6-pentafluorobenzyl) hydroxylamine and the 4-OH-CP oxime product analyzed by gas or liquid chromatography-mass spectroscopy. Separate blood draws (5 ml) were collected at ~24 and 48 hours following CP infusion in the transplant arm to determine white blood cell count (wbc). The single-dose PK parameters for CP and 4-OH-CP were computed from the drug C-T data using non-compartmental methods within WinNonLin Phoenix Version 6.2. Metabolic ratio was computed as the ratio of the AUC over 24h for 4-OH-CP to that for CP.

Results:

Of the 12 subjects in the transplant arm and 9 in the CP arm, 75-89% were Caucasian women of median age 44 and 49, respectively. While the metabolic ratio varied 14-fold (0.6 – 8.3), the CxT profiles for both treatment arms were similar with a single elimination phase for both CP and 4-OH-CP. In the CP arm, CxT profiles for both parent drug and active metabolite were very similar in both cycles 1 and 2. When normalized for dose, the median AUC for 4-OH-CP in cycles 1 and 2 were 173 and 171 µg-h/ml, hence there was no auto-activation. There was a significant Pearson product-moment correlation between decrease in wbc and metabolic ratio at 48 h (p = 0.026) in the transplant arm. Odds ratios via logistic regression among PK parameters and EFS were not statistically significant.

Odds Ratios – Likelihood of not meeting Event-Free Survival Endpoint¹

Arm	Parameter	Odds Ratio	Lower 95% CI	Upper 95% CI	P value
Cyclophosphamide	CP AUC24²	1.0	1.0	1.0	0.94
Cyclophosphamide	CP Cmax	1.1	0.8	1.7	0.51
Cyclophosphamide	Metabolic Ratio³	0.9	0.3	2.1	0.74
Cyclophosphamide	4-OH-PC AUC24	1.1	0.7	1.8	0.70
Cyclophosphamide	4-OH-CP Cmax	3.3	0.1	126.3	0.53
Transplant	CP AUC24	1.0	1.0	1.0	0.20
Transplant	CP Cmax	0.8	0.5	1.1	0.15
Transplant	Metabolic Ratio	1.8	0.5	6.7	0.36
Transplant	4-OH-CP AUC24	1.0	0.7	1.6	0.89
Transplant	4-OH-CP Cmax	1.2	0.1	12.5	0.91
¹Event-free survival is survival without respiratory, renal or cardiac failure as defined in Sullivan, KM et al., N Engl J Med 2018;378:35-47. ²AUC24, area under the concentration-time curve at 24 hrs. ³Ratio of AUC24 for 4-OH-CP to that for CP.

Conclusion:

This pilot study, the first of its kind, revealed variable metabolism of CP in scleroderma subjects and drug-induced myelosuppression in the transplant setting. However, in this small cohort of patients, CP exposure did not correlate with EFS in either treatment arm.

Disclosure: D. Adams, None; K. Sullivan, None; I. Spasojevic, None; P. Fan, None; M. Sampson, None; M. Cohen-Wolkowiez, None; E. W. St Clair, None; R. Woolson, None; J. Storek, None; M. E. Csuka, None; A. Pinckney, None; B. Welch, None; E. Goldmuntz, None; D. E. Furst, no stocks, 2, 5, 6, 7; L. Crofford, None; L. Keyes-Elstein, None; M. Mayes, None; P. McSweeney, None; R. Nash, None.

To cite this abstract in AMA style:

Adams D, Sullivan K, Spasojevic I, Fan P, Sampson M, Cohen-Wolkowiez M, St Clair EW, Woolson R, Storek J, Csuka ME, Pinckney A, Welch B, Goldmuntz E, Furst DE, Crofford L, Keyes-Elstein L, Mayes M, McSweeney P, Nash R. Pharmacokinetics of Cyclophosphamide in Scleroderma Treated By Cyclophosphamide Versus Transplantation [abstract]. Arthritis Rheumatol. 2018; 70 (suppl 9). https://acrabstracts.org/abstract/pharmacokinetics-of-cyclophosphamide-in-scleroderma-treated-by-cyclophosphamide-versus-transplantation/. Accessed .

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