Number: Su1822
USTEKINUMAB DRUG CLEARANCE IS BETTER ASSOCIATED WITH CROHN'S DISEASE REMISSION THAN SERUM TROUGH CONCENTRATIONS IN PROSPECTIVE COHORT STUDY
Society: AGA
Track: Inflammatory Bowel Diseases
Background: Ustekinumab (UST) has been found effective for the treatment of Crohn's disease (CD). However, some patients may respond insufficiently. Identifying pharmacokinetic (PK) mechanisms of non-response is important as dose optimization could recapture some of these failures. The aim of this study was to assess the association between measured UST serum concentrations and model-predicted UST serum clearance (CL) with CD clinical and biochemical remission in a real-world population.
Methods: This was a prospective cohort study performed in two centers that included patients that were on maintenance therapy with subcutaneous UST 90 mg every 4 to 8 weeks (W) after receiving one IV loading dose. Serial serum UST concentrations and antibodies to UST (ATU) were performed at trough and measured using a drug tolerant homogenous mobility shift assay (HMSA) through the follow-up. serum drug CL was calculated using a population PK model (DOI: 10.1111/bcp.14971) specifically reparametrized using HMSA UST concentrations and ATU status measured at the time of specimen collection. The primary outcome was combined clinical and biochemical remission defined as a Harvey Bradshaw Index <5 and a normal C-reactive protein (CRP <3 mg/L). Secondary outcome was a normal endoscopic healing index (EHI <20), a validated surrogate marker associated with intestinal endoscopic remission in CD. Receiver operating characteristics (ROC) curves with calculation of AUC, and logistic regression were performed.
Results: 80 patients with CD were enrolled (median age=42 [IQR: 28-58] years, median weight=76 [IQR: 62-87] Kg, 52% female) and evaluated across 308 UST dose cycles (3.9 cycles per patient, n=92 cycles with every 4W interdose interval). Median UST concentration and CL were 4.9 µg/mL (IQR: 3.0-8.5 µg/mL) and 0.152 L/day (IQR: 0.122-0.185 L/day), respectively. Clinical + biochemical remission and a EHI < 20 had been achieved in 28% and 21% of the cycles, respectively. No ATU was detected in any sample. In the ROC analysis, UST CL was better associated with remission than concentrations (AUC=0.696±0.032 vs 0.626±0.035; p=0.017). The trough concentration and drug CL cutoffs best associated with remission were >4.5 µg/mL and <0.156 L/day, respectively. At those thresholds, there was a 1.7-fold (95%CI: 1.0-2.9; p=0.038) and 5.6-fold (95%CI: 3.1-10.3; p<0.001) higher likelihood of achieving remission, for concentrations and CL, respectively (Figure 1). Similar results were observed with the EHI (OR=2.43 95%CI: 1.34- 4.4, p=0.003 and OR=2.03 95%CI: 1.14,3.6; p=0.016; respectively).
Conclusion: The calculation of UST CL may offer a better value when using TDM in patients with non-response to UST and adds to the body of evidence that this outcome measure may be more clinically relevant than concentrations themselves.
Number: Su1822
USTEKINUMAB DRUG CLEARANCE IS BETTER ASSOCIATED WITH CROHN'S DISEASE REMISSION THAN SERUM TROUGH CONCENTRATIONS IN PROSPECTIVE COHORT STUDY
Society: AGA
Track: Inflammatory Bowel Diseases
Background: Ustekinumab (UST) has been found effective for the treatment of Crohn's disease (CD). However, some patients may respond insufficiently. Identifying pharmacokinetic (PK) mechanisms of non-response is important as dose optimization could recapture some of these failures. The aim of this study was to assess the association between measured UST serum concentrations and model-predicted UST serum clearance (CL) with CD clinical and biochemical remission in a real-world population.
Methods: This was a prospective cohort study performed in two centers that included patients that were on maintenance therapy with subcutaneous UST 90 mg every 4 to 8 weeks (W) after receiving one IV loading dose. Serial serum UST concentrations and antibodies to UST (ATU) were performed at trough and measured using a drug tolerant homogenous mobility shift assay (HMSA) through the follow-up. serum drug CL was calculated using a population PK model (DOI: 10.1111/bcp.14971) specifically reparametrized using HMSA UST concentrations and ATU status measured at the time of specimen collection. The primary outcome was combined clinical and biochemical remission defined as a Harvey Bradshaw Index <5 and a normal C-reactive protein (CRP <3 mg/L). Secondary outcome was a normal endoscopic healing index (EHI <20), a validated surrogate marker associated with intestinal endoscopic remission in CD. Receiver operating characteristics (ROC) curves with calculation of AUC, and logistic regression were performed.
Results: 80 patients with CD were enrolled (median age=42 [IQR: 28-58] years, median weight=76 [IQR: 62-87] Kg, 52% female) and evaluated across 308 UST dose cycles (3.9 cycles per patient, n=92 cycles with every 4W interdose interval). Median UST concentration and CL were 4.9 µg/mL (IQR: 3.0-8.5 µg/mL) and 0.152 L/day (IQR: 0.122-0.185 L/day), respectively. Clinical + biochemical remission and a EHI < 20 had been achieved in 28% and 21% of the cycles, respectively. No ATU was detected in any sample. In the ROC analysis, UST CL was better associated with remission than concentrations (AUC=0.696±0.032 vs 0.626±0.035; p=0.017). The trough concentration and drug CL cutoffs best associated with remission were >4.5 µg/mL and <0.156 L/day, respectively. At those thresholds, there was a 1.7-fold (95%CI: 1.0-2.9; p=0.038) and 5.6-fold (95%CI: 3.1-10.3; p<0.001) higher likelihood of achieving remission, for concentrations and CL, respectively (Figure 1). Similar results were observed with the EHI (OR=2.43 95%CI: 1.34- 4.4, p=0.003 and OR=2.03 95%CI: 1.14,3.6; p=0.016; respectively).
Conclusion: The calculation of UST CL may offer a better value when using TDM in patients with non-response to UST and adds to the body of evidence that this outcome measure may be more clinically relevant than concentrations themselves.
Number: Su1822
USTEKINUMAB DRUG CLEARANCE IS BETTER ASSOCIATED WITH CROHN'S DISEASE REMISSION THAN SERUM TROUGH CONCENTRATIONS IN PROSPECTIVE COHORT STUDY
Society: AGA
Track: Inflammatory Bowel Diseases
Background: Ustekinumab (UST) has been found effective for the treatment of Crohn's disease (CD). However, some patients may respond insufficiently. Identifying pharmacokinetic (PK) mechanisms of non-response is important as dose optimization could recapture some of these failures. The aim of this study was to assess the association between measured UST serum concentrations and model-predicted UST serum clearance (CL) with CD clinical and biochemical remission in a real-world population.
Methods: This was a prospective cohort study performed in two centers that included patients that were on maintenance therapy with subcutaneous UST 90 mg every 4 to 8 weeks (W) after receiving one IV loading dose. Serial serum UST concentrations and antibodies to UST (ATU) were performed at trough and measured using a drug tolerant homogenous mobility shift assay (HMSA) through the follow-up. serum drug CL was calculated using a population PK model (DOI: 10.1111/bcp.14971) specifically reparametrized using HMSA UST concentrations and ATU status measured at the time of specimen collection. The primary outcome was combined clinical and biochemical remission defined as a Harvey Bradshaw Index <5 and a normal C-reactive protein (CRP <3 mg/L). Secondary outcome was a normal endoscopic healing index (EHI <20), a validated surrogate marker associated with intestinal endoscopic remission in CD. Receiver operating characteristics (ROC) curves with calculation of AUC, and logistic regression were performed.
Results: 80 patients with CD were enrolled (median age=42 [IQR: 28-58] years, median weight=76 [IQR: 62-87] Kg, 52% female) and evaluated across 308 UST dose cycles (3.9 cycles per patient, n=92 cycles with every 4W interdose interval). Median UST concentration and CL were 4.9 µg/mL (IQR: 3.0-8.5 µg/mL) and 0.152 L/day (IQR: 0.122-0.185 L/day), respectively. Clinical + biochemical remission and a EHI < 20 had been achieved in 28% and 21% of the cycles, respectively. No ATU was detected in any sample. In the ROC analysis, UST CL was better associated with remission than concentrations (AUC=0.696±0.032 vs 0.626±0.035; p=0.017). The trough concentration and drug CL cutoffs best associated with remission were >4.5 µg/mL and <0.156 L/day, respectively. At those thresholds, there was a 1.7-fold (95%CI: 1.0-2.9; p=0.038) and 5.6-fold (95%CI: 3.1-10.3; p<0.001) higher likelihood of achieving remission, for concentrations and CL, respectively (Figure 1). Similar results were observed with the EHI (OR=2.43 95%CI: 1.34- 4.4, p=0.003 and OR=2.03 95%CI: 1.14,3.6; p=0.016; respectively).
Conclusion: The calculation of UST CL may offer a better value when using TDM in patients with non-response to UST and adds to the body of evidence that this outcome measure may be more clinically relevant than concentrations themselves.
Number: Su1822
USTEKINUMAB DRUG CLEARANCE IS BETTER ASSOCIATED WITH CROHN'S DISEASE REMISSION THAN SERUM TROUGH CONCENTRATIONS IN PROSPECTIVE COHORT STUDY
Society: AGA
Track: Inflammatory Bowel Diseases
Background: Ustekinumab (UST) has been found effective for the treatment of Crohn's disease (CD). However, some patients may respond insufficiently. Identifying pharmacokinetic (PK) mechanisms of non-response is important as dose optimization could recapture some of these failures. The aim of this study was to assess the association between measured UST serum concentrations and model-predicted UST serum clearance (CL) with CD clinical and biochemical remission in a real-world population.
Methods: This was a prospective cohort study performed in two centers that included patients that were on maintenance therapy with subcutaneous UST 90 mg every 4 to 8 weeks (W) after receiving one IV loading dose. Serial serum UST concentrations and antibodies to UST (ATU) were performed at trough and measured using a drug tolerant homogenous mobility shift assay (HMSA) through the follow-up. serum drug CL was calculated using a population PK model (DOI: 10.1111/bcp.14971) specifically reparametrized using HMSA UST concentrations and ATU status measured at the time of specimen collection. The primary outcome was combined clinical and biochemical remission defined as a Harvey Bradshaw Index <5 and a normal C-reactive protein (CRP <3 mg/L). Secondary outcome was a normal endoscopic healing index (EHI <20), a validated surrogate marker associated with intestinal endoscopic remission in CD. Receiver operating characteristics (ROC) curves with calculation of AUC, and logistic regression were performed.
Results: 80 patients with CD were enrolled (median age=42 [IQR: 28-58] years, median weight=76 [IQR: 62-87] Kg, 52% female) and evaluated across 308 UST dose cycles (3.9 cycles per patient, n=92 cycles with every 4W interdose interval). Median UST concentration and CL were 4.9 µg/mL (IQR: 3.0-8.5 µg/mL) and 0.152 L/day (IQR: 0.122-0.185 L/day), respectively. Clinical + biochemical remission and a EHI < 20 had been achieved in 28% and 21% of the cycles, respectively. No ATU was detected in any sample. In the ROC analysis, UST CL was better associated with remission than concentrations (AUC=0.696±0.032 vs 0.626±0.035; p=0.017). The trough concentration and drug CL cutoffs best associated with remission were >4.5 µg/mL and <0.156 L/day, respectively. At those thresholds, there was a 1.7-fold (95%CI: 1.0-2.9; p=0.038) and 5.6-fold (95%CI: 3.1-10.3; p<0.001) higher likelihood of achieving remission, for concentrations and CL, respectively (Figure 1). Similar results were observed with the EHI (OR=2.43 95%CI: 1.34- 4.4, p=0.003 and OR=2.03 95%CI: 1.14,3.6; p=0.016; respectively).
Conclusion: The calculation of UST CL may offer a better value when using TDM in patients with non-response to UST and adds to the body of evidence that this outcome measure may be more clinically relevant than concentrations themselves.