Abstract
Background: Baseline Clearance (CL) of Infliximab (IFX) is known to associate with colectomy in acute severe ulcerative colitis (1). We evaluated the impact of accelerated CL before starting treatment on the lack of disease control achieved during maintenance of Crohn’s disease (CD) patients treated with adalimumab (ADA) and IFX.
Methods: Baseline CL was estimated before starting treatment using weight (Kg) and serum Albumin (ALB) concentrations from previously published population PK model of patients receiving IFX (2). Baseline CL for Adalimumab (ADA) was estimated using population PK model from training cohort of 113 consented CD starting treatment and followed longitudinally during their maintenance. Outcome consisted of sustained CRP based clinical remission status achieved (corresponding to CRP concentration below 3 mg/L in the absence of symptoms [CDAI<150 points]) in training cohort. Replication was tested in two cohorts, a first CD cohort (STRIDENT) (3) who received ADA with similar outcome collected, and a second cohort from PANTS where CD received IFX and ADA using the definition of non-response at 52 weeks (4). Population estimates of CL or apparent CL for IFX and ADA, respectively, were used (0.294 L/day, and 0.326 L/day, respectively) to calculate the performances of baseline CL in distinguishing lack of disease control during maintenance. Statistical analysis consisted of ROC analysis, logistic regression.
Results: Baseline CL for IFX and ADA distinguished lack of disease control achieved in the training cohort with AUC of 0.707 (95%CI: 0.606-0.809) and 0.701 (95%CI: 0.606-0.809), respectively. Baseline IFX and ADA CL above population cutoff, yielded 4.4-fold (1.7 to 11.2) and 10.4-fold (95%CI: 2.5-41.9) higher likelihood for non-response for ADA treated patients, a finding that replicated in STRIDENT (p<0.05) (Table). Baseline CL for IFX and ADA also associated with outcome in PANTS where accelerated CL for IFX and ADA yielded 3.0-fold (95%CI: 1.9 to 5.0) and 2.2-fold (95%CI: 1.3 to 3.8) higher likelihood of non-response for the ADA treated patients, respectively, with lesser significance achieved for the IFX treated patients. Results are presented in Table I. CL for IFX and ADA in relation to the lack of disease control is presented in Figure 1.
Conclusion: Baseline CL for monoclonal antibodies associate with disease control in CD treated with anti-TNF and likely reflects intrinsic suboptimal PK as well as inflammatory burden consuming the drug.
References:
Battat et al., Clin Gastroenterol Hepatol. 2021 Mar;19(3):511-518.e6.
Dubinsky et al, AAPS J. 2017 doi: 10.1208/s12248-016-9994-y.
Schulberg et al., Lancet Gastroenterol Hepatol. 2022 doi: 10.1016/S2468-1253(21)00393-
Kennedy et al. Lancet Gastroenterol Hepatol. 2019 doi: 10.1016/S2468-1253(19)30012-3
Methods: Baseline CL was estimated before starting treatment using weight (Kg) and serum Albumin (ALB) concentrations from previously published population PK model of patients receiving IFX (2). Baseline CL for Adalimumab (ADA) was estimated using population PK model from training cohort of 113 consented CD starting treatment and followed longitudinally during their maintenance. Outcome consisted of sustained CRP based clinical remission status achieved (corresponding to CRP concentration below 3 mg/L in the absence of symptoms [CDAI<150 points]) in training cohort. Replication was tested in two cohorts, a first CD cohort (STRIDENT) (3) who received ADA with similar outcome collected, and a second cohort from PANTS where CD received IFX and ADA using the definition of non-response at 52 weeks (4). Population estimates of CL or apparent CL for IFX and ADA, respectively, were used (0.294 L/day, and 0.326 L/day, respectively) to calculate the performances of baseline CL in distinguishing lack of disease control during maintenance. Statistical analysis consisted of ROC analysis, logistic regression.
Results: Baseline CL for IFX and ADA distinguished lack of disease control achieved in the training cohort with AUC of 0.707 (95%CI: 0.606-0.809) and 0.701 (95%CI: 0.606-0.809), respectively. Baseline IFX and ADA CL above population cutoff, yielded 4.4-fold (1.7 to 11.2) and 10.4-fold (95%CI: 2.5-41.9) higher likelihood for non-response for ADA treated patients, a finding that replicated in STRIDENT (p<0.05) (Table). Baseline CL for IFX and ADA also associated with outcome in PANTS where accelerated CL for IFX and ADA yielded 3.0-fold (95%CI: 1.9 to 5.0) and 2.2-fold (95%CI: 1.3 to 3.8) higher likelihood of non-response for the ADA treated patients, respectively, with lesser significance achieved for the IFX treated patients. Results are presented in Table I. CL for IFX and ADA in relation to the lack of disease control is presented in Figure 1.
Conclusion: Baseline CL for monoclonal antibodies associate with disease control in CD treated with anti-TNF and likely reflects intrinsic suboptimal PK as well as inflammatory burden consuming the drug.
References:
Battat et al., Clin Gastroenterol Hepatol. 2021 Mar;19(3):511-518.e6.
Dubinsky et al, AAPS J. 2017 doi: 10.1208/s12248-016-9994-y.
Schulberg et al., Lancet Gastroenterol Hepatol. 2022 doi: 10.1016/S2468-1253(21)00393-
Kennedy et al. Lancet Gastroenterol Hepatol. 2019 doi: 10.1016/S2468-1253(19)30012-3
Background: Baseline Clearance (CL) of Infliximab (IFX) is known to associate with colectomy in acute severe ulcerative colitis (1). We evaluated the impact of accelerated CL before starting treatment on the lack of disease control achieved during maintenance of Crohn’s disease (CD) patients treated with adalimumab (ADA) and IFX.
Methods: Baseline CL was estimated before starting treatment using weight (Kg) and serum Albumin (ALB) concentrations from previously published population PK model of patients receiving IFX (2). Baseline CL for Adalimumab (ADA) was estimated using population PK model from training cohort of 113 consented CD starting treatment and followed longitudinally during their maintenance. Outcome consisted of sustained CRP based clinical remission status achieved (corresponding to CRP concentration below 3 mg/L in the absence of symptoms [CDAI<150 points]) in training cohort. Replication was tested in two cohorts, a first CD cohort (STRIDENT) (3) who received ADA with similar outcome collected, and a second cohort from PANTS where CD received IFX and ADA using the definition of non-response at 52 weeks (4). Population estimates of CL or apparent CL for IFX and ADA, respectively, were used (0.294 L/day, and 0.326 L/day, respectively) to calculate the performances of baseline CL in distinguishing lack of disease control during maintenance. Statistical analysis consisted of ROC analysis, logistic regression.
Results: Baseline CL for IFX and ADA distinguished lack of disease control achieved in the training cohort with AUC of 0.707 (95%CI: 0.606-0.809) and 0.701 (95%CI: 0.606-0.809), respectively. Baseline IFX and ADA CL above population cutoff, yielded 4.4-fold (1.7 to 11.2) and 10.4-fold (95%CI: 2.5-41.9) higher likelihood for non-response for ADA treated patients, a finding that replicated in STRIDENT (p<0.05) (Table). Baseline CL for IFX and ADA also associated with outcome in PANTS where accelerated CL for IFX and ADA yielded 3.0-fold (95%CI: 1.9 to 5.0) and 2.2-fold (95%CI: 1.3 to 3.8) higher likelihood of non-response for the ADA treated patients, respectively, with lesser significance achieved for the IFX treated patients. Results are presented in Table I. CL for IFX and ADA in relation to the lack of disease control is presented in Figure 1.
Conclusion: Baseline CL for monoclonal antibodies associate with disease control in CD treated with anti-TNF and likely reflects intrinsic suboptimal PK as well as inflammatory burden consuming the drug.
References:
Battat et al., Clin Gastroenterol Hepatol. 2021 Mar;19(3):511-518.e6.
Dubinsky et al, AAPS J. 2017 doi: 10.1208/s12248-016-9994-y.
Schulberg et al., Lancet Gastroenterol Hepatol. 2022 doi: 10.1016/S2468-1253(21)00393-
Kennedy et al. Lancet Gastroenterol Hepatol. 2019 doi: 10.1016/S2468-1253(19)30012-3
Methods: Baseline CL was estimated before starting treatment using weight (Kg) and serum Albumin (ALB) concentrations from previously published population PK model of patients receiving IFX (2). Baseline CL for Adalimumab (ADA) was estimated using population PK model from training cohort of 113 consented CD starting treatment and followed longitudinally during their maintenance. Outcome consisted of sustained CRP based clinical remission status achieved (corresponding to CRP concentration below 3 mg/L in the absence of symptoms [CDAI<150 points]) in training cohort. Replication was tested in two cohorts, a first CD cohort (STRIDENT) (3) who received ADA with similar outcome collected, and a second cohort from PANTS where CD received IFX and ADA using the definition of non-response at 52 weeks (4). Population estimates of CL or apparent CL for IFX and ADA, respectively, were used (0.294 L/day, and 0.326 L/day, respectively) to calculate the performances of baseline CL in distinguishing lack of disease control during maintenance. Statistical analysis consisted of ROC analysis, logistic regression.
Results: Baseline CL for IFX and ADA distinguished lack of disease control achieved in the training cohort with AUC of 0.707 (95%CI: 0.606-0.809) and 0.701 (95%CI: 0.606-0.809), respectively. Baseline IFX and ADA CL above population cutoff, yielded 4.4-fold (1.7 to 11.2) and 10.4-fold (95%CI: 2.5-41.9) higher likelihood for non-response for ADA treated patients, a finding that replicated in STRIDENT (p<0.05) (Table). Baseline CL for IFX and ADA also associated with outcome in PANTS where accelerated CL for IFX and ADA yielded 3.0-fold (95%CI: 1.9 to 5.0) and 2.2-fold (95%CI: 1.3 to 3.8) higher likelihood of non-response for the ADA treated patients, respectively, with lesser significance achieved for the IFX treated patients. Results are presented in Table I. CL for IFX and ADA in relation to the lack of disease control is presented in Figure 1.
Conclusion: Baseline CL for monoclonal antibodies associate with disease control in CD treated with anti-TNF and likely reflects intrinsic suboptimal PK as well as inflammatory burden consuming the drug.
References:
Battat et al., Clin Gastroenterol Hepatol. 2021 Mar;19(3):511-518.e6.
Dubinsky et al, AAPS J. 2017 doi: 10.1208/s12248-016-9994-y.
Schulberg et al., Lancet Gastroenterol Hepatol. 2022 doi: 10.1016/S2468-1253(21)00393-
Kennedy et al. Lancet Gastroenterol Hepatol. 2019 doi: 10.1016/S2468-1253(19)30012-3
BASELINE CLEARANCE FOR ANTI TUMOR NECROSIS FACTORS PREDICTS LACK OF DISEASE CONTROL DURING MAINTENANCE TREATMENT OF CROHN’S DISEASE WITH INFLIXIMAB AND ADALIMUMAB
Dermot P.B. Mcgovern
Abstract
Background: Baseline Clearance (CL) of Infliximab (IFX) is known to associate with colectomy in acute severe ulcerative colitis (1). We evaluated the impact of accelerated CL before starting treatment on the lack of disease control achieved during maintenance of Crohn’s disease (CD) patients treated with adalimumab (ADA) and IFX.
Methods: Baseline CL was estimated before starting treatment using weight (Kg) and serum Albumin (ALB) concentrations from previously published population PK model of patients receiving IFX (2). Baseline CL for Adalimumab (ADA) was estimated using population PK model from training cohort of 113 consented CD starting treatment and followed longitudinally during their maintenance. Outcome consisted of sustained CRP based clinical remission status achieved (corresponding to CRP concentration below 3 mg/L in the absence of symptoms [CDAI<150 points]) in training cohort. Replication was tested in two cohorts, a first CD cohort (STRIDENT) (3) who received ADA with similar outcome collected, and a second cohort from PANTS where CD received IFX and ADA using the definition of non-response at 52 weeks (4). Population estimates of CL or apparent CL for IFX and ADA, respectively, were used (0.294 L/day, and 0.326 L/day, respectively) to calculate the performances of baseline CL in distinguishing lack of disease control during maintenance. Statistical analysis consisted of ROC analysis, logistic regression.
Results: Baseline CL for IFX and ADA distinguished lack of disease control achieved in the training cohort with AUC of 0.707 (95%CI: 0.606-0.809) and 0.701 (95%CI: 0.606-0.809), respectively. Baseline IFX and ADA CL above population cutoff, yielded 4.4-fold (1.7 to 11.2) and 10.4-fold (95%CI: 2.5-41.9) higher likelihood for non-response for ADA treated patients, a finding that replicated in STRIDENT (p<0.05) (Table). Baseline CL for IFX and ADA also associated with outcome in PANTS where accelerated CL for IFX and ADA yielded 3.0-fold (95%CI: 1.9 to 5.0) and 2.2-fold (95%CI: 1.3 to 3.8) higher likelihood of non-response for the ADA treated patients, respectively, with lesser significance achieved for the IFX treated patients. Results are presented in Table I. CL for IFX and ADA in relation to the lack of disease control is presented in Figure 1.
Conclusion: Baseline CL for monoclonal antibodies associate with disease control in CD treated with anti-TNF and likely reflects intrinsic suboptimal PK as well as inflammatory burden consuming the drug.
References:
Battat et al., Clin Gastroenterol Hepatol. 2021 Mar;19(3):511-518.e6.
Dubinsky et al, AAPS J. 2017 doi: 10.1208/s12248-016-9994-y.
Schulberg et al., Lancet Gastroenterol Hepatol. 2022 doi: 10.1016/S2468-1253(21)00393-
Kennedy et al. Lancet Gastroenterol Hepatol. 2019 doi: 10.1016/S2468-1253(19)30012-3
Methods: Baseline CL was estimated before starting treatment using weight (Kg) and serum Albumin (ALB) concentrations from previously published population PK model of patients receiving IFX (2). Baseline CL for Adalimumab (ADA) was estimated using population PK model from training cohort of 113 consented CD starting treatment and followed longitudinally during their maintenance. Outcome consisted of sustained CRP based clinical remission status achieved (corresponding to CRP concentration below 3 mg/L in the absence of symptoms [CDAI<150 points]) in training cohort. Replication was tested in two cohorts, a first CD cohort (STRIDENT) (3) who received ADA with similar outcome collected, and a second cohort from PANTS where CD received IFX and ADA using the definition of non-response at 52 weeks (4). Population estimates of CL or apparent CL for IFX and ADA, respectively, were used (0.294 L/day, and 0.326 L/day, respectively) to calculate the performances of baseline CL in distinguishing lack of disease control during maintenance. Statistical analysis consisted of ROC analysis, logistic regression.
Results: Baseline CL for IFX and ADA distinguished lack of disease control achieved in the training cohort with AUC of 0.707 (95%CI: 0.606-0.809) and 0.701 (95%CI: 0.606-0.809), respectively. Baseline IFX and ADA CL above population cutoff, yielded 4.4-fold (1.7 to 11.2) and 10.4-fold (95%CI: 2.5-41.9) higher likelihood for non-response for ADA treated patients, a finding that replicated in STRIDENT (p<0.05) (Table). Baseline CL for IFX and ADA also associated with outcome in PANTS where accelerated CL for IFX and ADA yielded 3.0-fold (95%CI: 1.9 to 5.0) and 2.2-fold (95%CI: 1.3 to 3.8) higher likelihood of non-response for the ADA treated patients, respectively, with lesser significance achieved for the IFX treated patients. Results are presented in Table I. CL for IFX and ADA in relation to the lack of disease control is presented in Figure 1.
Conclusion: Baseline CL for monoclonal antibodies associate with disease control in CD treated with anti-TNF and likely reflects intrinsic suboptimal PK as well as inflammatory burden consuming the drug.
References:
Battat et al., Clin Gastroenterol Hepatol. 2021 Mar;19(3):511-518.e6.
Dubinsky et al, AAPS J. 2017 doi: 10.1208/s12248-016-9994-y.
Schulberg et al., Lancet Gastroenterol Hepatol. 2022 doi: 10.1016/S2468-1253(21)00393-
Kennedy et al. Lancet Gastroenterol Hepatol. 2019 doi: 10.1016/S2468-1253(19)30012-3
Background: Baseline Clearance (CL) of Infliximab (IFX) is known to associate with colectomy in acute severe ulcerative colitis (1). We evaluated the impact of accelerated CL before starting treatment on the lack of disease control achieved during maintenance of Crohn’s disease (CD) patients treated with adalimumab (ADA) and IFX.
Methods: Baseline CL was estimated before starting treatment using weight (Kg) and serum Albumin (ALB) concentrations from previously published population PK model of patients receiving IFX (2). Baseline CL for Adalimumab (ADA) was estimated using population PK model from training cohort of 113 consented CD starting treatment and followed longitudinally during their maintenance. Outcome consisted of sustained CRP based clinical remission status achieved (corresponding to CRP concentration below 3 mg/L in the absence of symptoms [CDAI<150 points]) in training cohort. Replication was tested in two cohorts, a first CD cohort (STRIDENT) (3) who received ADA with similar outcome collected, and a second cohort from PANTS where CD received IFX and ADA using the definition of non-response at 52 weeks (4). Population estimates of CL or apparent CL for IFX and ADA, respectively, were used (0.294 L/day, and 0.326 L/day, respectively) to calculate the performances of baseline CL in distinguishing lack of disease control during maintenance. Statistical analysis consisted of ROC analysis, logistic regression.
Results: Baseline CL for IFX and ADA distinguished lack of disease control achieved in the training cohort with AUC of 0.707 (95%CI: 0.606-0.809) and 0.701 (95%CI: 0.606-0.809), respectively. Baseline IFX and ADA CL above population cutoff, yielded 4.4-fold (1.7 to 11.2) and 10.4-fold (95%CI: 2.5-41.9) higher likelihood for non-response for ADA treated patients, a finding that replicated in STRIDENT (p<0.05) (Table). Baseline CL for IFX and ADA also associated with outcome in PANTS where accelerated CL for IFX and ADA yielded 3.0-fold (95%CI: 1.9 to 5.0) and 2.2-fold (95%CI: 1.3 to 3.8) higher likelihood of non-response for the ADA treated patients, respectively, with lesser significance achieved for the IFX treated patients. Results are presented in Table I. CL for IFX and ADA in relation to the lack of disease control is presented in Figure 1.
Conclusion: Baseline CL for monoclonal antibodies associate with disease control in CD treated with anti-TNF and likely reflects intrinsic suboptimal PK as well as inflammatory burden consuming the drug.
References:
Battat et al., Clin Gastroenterol Hepatol. 2021 Mar;19(3):511-518.e6.
Dubinsky et al, AAPS J. 2017 doi: 10.1208/s12248-016-9994-y.
Schulberg et al., Lancet Gastroenterol Hepatol. 2022 doi: 10.1016/S2468-1253(21)00393-
Kennedy et al. Lancet Gastroenterol Hepatol. 2019 doi: 10.1016/S2468-1253(19)30012-3
Methods: Baseline CL was estimated before starting treatment using weight (Kg) and serum Albumin (ALB) concentrations from previously published population PK model of patients receiving IFX (2). Baseline CL for Adalimumab (ADA) was estimated using population PK model from training cohort of 113 consented CD starting treatment and followed longitudinally during their maintenance. Outcome consisted of sustained CRP based clinical remission status achieved (corresponding to CRP concentration below 3 mg/L in the absence of symptoms [CDAI<150 points]) in training cohort. Replication was tested in two cohorts, a first CD cohort (STRIDENT) (3) who received ADA with similar outcome collected, and a second cohort from PANTS where CD received IFX and ADA using the definition of non-response at 52 weeks (4). Population estimates of CL or apparent CL for IFX and ADA, respectively, were used (0.294 L/day, and 0.326 L/day, respectively) to calculate the performances of baseline CL in distinguishing lack of disease control during maintenance. Statistical analysis consisted of ROC analysis, logistic regression.
Results: Baseline CL for IFX and ADA distinguished lack of disease control achieved in the training cohort with AUC of 0.707 (95%CI: 0.606-0.809) and 0.701 (95%CI: 0.606-0.809), respectively. Baseline IFX and ADA CL above population cutoff, yielded 4.4-fold (1.7 to 11.2) and 10.4-fold (95%CI: 2.5-41.9) higher likelihood for non-response for ADA treated patients, a finding that replicated in STRIDENT (p<0.05) (Table). Baseline CL for IFX and ADA also associated with outcome in PANTS where accelerated CL for IFX and ADA yielded 3.0-fold (95%CI: 1.9 to 5.0) and 2.2-fold (95%CI: 1.3 to 3.8) higher likelihood of non-response for the ADA treated patients, respectively, with lesser significance achieved for the IFX treated patients. Results are presented in Table I. CL for IFX and ADA in relation to the lack of disease control is presented in Figure 1.
Conclusion: Baseline CL for monoclonal antibodies associate with disease control in CD treated with anti-TNF and likely reflects intrinsic suboptimal PK as well as inflammatory burden consuming the drug.
References:
Battat et al., Clin Gastroenterol Hepatol. 2021 Mar;19(3):511-518.e6.
Dubinsky et al, AAPS J. 2017 doi: 10.1208/s12248-016-9994-y.
Schulberg et al., Lancet Gastroenterol Hepatol. 2022 doi: 10.1016/S2468-1253(21)00393-
Kennedy et al. Lancet Gastroenterol Hepatol. 2019 doi: 10.1016/S2468-1253(19)30012-3
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