A Review of the Clinical Pharmacokinetics, Pharmacodynamics, and Immunogenicity of Vedolizumab

Vedolizumab was administered as a single IV infusion to healthy volunteers on a body weight-adjusted basis over the dose range of 0.2–10.0 mg/kg in a phase I study [25]. After reaching peak concentrations, vedolizumab serum concentrations declined in a generally linear fashion until concentrations reached approximately 10 µg/mL (Fig. 1). Thereafter, concentrations appeared to decline in a non-linear fashion. Vedolizumab maximum observed serum concentration (C _max) was dose proportional over the dose range tested (Table 1). Greater than dose-proportional increases in the vedolizumab area under the serum concentration–time curve (AUC) from time zero to infinity (AUC_0−∞) and dose-dependent decreases in clearance (CL) and increases in terminal elimination half-life (t _½ β) were observed from 0.2 to 2.0 mg/kg (Table 1). At dose levels >2.0 mg/kg, the increases in AUC_0−∞ were dose proportional and CL and t _½ did not change. These data suggest that a rapid elimination process becomes saturated as the vedolizumab dose increases, and slower linear elimination processes likely account for a large fraction of vedolizumab CL at higher concentrations.

Vedolizumab was also administered as a single IV infusion to healthy volunteers on a fixed-dose basis over the dose range of 180–750 mg. Comparison of the data across these studies revealed that vedolizumab exposure increased in a dose-proportional manner at doses >180 mg (Table 2). The apparent linear pharmacokinetics at doses >180 mg (equivalent to 2.4 mg/kg in a 75 kg individual) is consistent with the data from the healthy volunteer study with body weight-adjusted (mg/kg) dosing.

The pharmacokinetics of vedolizumab following repeat IV infusions were evaluated in patients with UC or CD over the dose range of 0.5–10 mg/kg in phase II studies [26‐28]. In patients with UC, vedolizumab concentrations increased with increasing dose over the range of 2–10 mg/kg, after an IV infusion on days 1, 15, 29, and 85 [27]. After the last dose on day 85, vedolizumab concentrations decreased in an approximately bi-exponential fashion. The pharmacokinetics of vedolizumab were dose proportional over the 2–10 mg/kg dose range based on C _max and AUC during the dosing interval (AUCτ) after dosing on days 1 and 85 (Table 3).

The pharmacokinetics of vedolizumab in patients with UC or CD were also assessed in the phase III GEMINI studies using a sparse (population-based) sampling scheme. During GEMINI 1 and GEMINI 2, patients received a 300 mg IV infusion of vedolizumab at weeks 0, and 2, (induction phase) and every 4 or 8 weeks thereafter starting at week 6 (maintenance phase) [11, 12]. During GEMINI 3, patients received a 300 mg IV infusion of vedolizumab at weeks 0, 2, and 6 (induction only) [13]. At week 6, mean vedolizumab trough serum concentrations were similar in patients with UC in GEMINI 1 and in patients with CD in GEMINI 2 and GEMINI 3 (Table 4). During the maintenance phases of both GEMINI 1 and GEMINI 2, the last vedolizumab trough concentration was measured at week 46 and was used to represent the end-of-treatment, steady-state trough concentration. At week 46, the mean vedolizumab trough concentration was higher in patients who received vedolizumab every 4 weeks than in patients who received vedolizumab every 8 weeks in both studies (Table 4).

The median trough serum concentration–time profile for each treatment regimen during the maintenance phase of GEMINI 1 and GEMINI 2 has been previously reported [29]. Patients who received two doses of vedolizumab during induction and placebo during maintenance had measurable vedolizumab trough concentrations in serum until week 38.

From the population pharmacokinetic analysis, the pharmacokinetics of vedolizumab were best described by a two-compartment model with zero-order input and parallel linear and non-linear elimination, similar to that described for other therapeutic monoclonal antibodies [29, 30]. The non-linear elimination process was modeled using a Michaelis–Menten equation. The overall inter-individual variability was moderate to large [29]. The effects of intrinsic and extrinsic factors on the pharmacokinetics of vedolizumab were investigated using a full covariate modeling approach [29, 31]. Inferences about the clinical relevance of parameters were based on the resulting parameter estimates and measures of estimation precision [Bayesian 95% credible intervals (CDIs)] from the final model. Covariate effect sizes on linear CL (CL_L) of less than ±25% from the typical population value, when evaluated over a representative range of covariate values, were not considered clinically relevant changes [29]. Pharmacokinetic parameter estimates derived from the model are described in Sects. 4.4–4.6, as are the effects of covariates on vedolizumab CL_L.

The vedolizumab volume of distribution at steady state (V _ss) after a single IV infusion of 300 mg in healthy volunteers was estimated to be 4.49 L [percent coefficient of variation (%CV) 14.3%] (Table 2). From the final population pharmacokinetic model, vedolizumab V _ss was estimated to be 4.84 L for both patients with UC and patients with CD [volume of distribution in the central compartment (V _c) = 3.19 L plus volume of distribution in the peripheral compartment (V _p) = 1.65 L] [29]. The V _ss values estimated for vedolizumab are approximately equal to the volume of plasma in humans and are generally similar to those reported for other therapeutic monoclonal antibodies [32]. After a single IV infusion of vedolizumab 450 mg in healthy volunteers, vedolizumab was not detected in the cerebrospinal fluid, suggesting that vedolizumab does not penetrate the blood–brain barrier [15].

Because of their large molecular size, therapeutic monoclonal antibodies are not directly excreted in urine; rather they are degraded to peptides and amino acids that are either reused by the body or excreted by the kidneys [32]. Several mechanisms are reportedly involved in the elimination of monoclonal antibodies, including proteolytic degradation by the liver or reticuloendothelial system, target-mediated elimination, and non-specific endocytosis [32]. Vedolizumab undergoes a rapid, saturable, non-linear, target-mediated elimination process at low concentrations and a slower, linear, non-specific elimination process at higher concentrations. From the final population pharmacokinetic model, the t _½ of vedolizumab was estimated to be 25.5 days, which only accounts for elimination through the linear process [29]. Estimates of t _½ obtained from non-compartmental analyses in the phase I and phase II studies account for elimination through both linear and non-linear processes (Tables 1, 2) and, therefore, are slightly lower than the estimate obtained from population pharmacokinetic modeling. Population estimates of CL_L were 0.159 L/day for patients with UC and 0.155 L/day for patients with CD [29]. Non-linear elimination was described by a maximum elimination rate (V _max) of 0.265 mg/day and concentration at half V _max (K _m) of 0.964 µg/mL [29]. The relationship between non-linear, linear, and total CL values across a range of vedolizumab concentrations is depicted in Fig. 2. At therapeutic concentrations, as indicated by trough concentration at steady state from dosing every 8 weeks (>10 μg/mL) [7], vedolizumab is eliminated primarily through the linear pathway.

No clinical studies have directly assessed the impact of vedolizumab administration on the pharmacokinetics of other drugs. Classic drug–drug interactions mediated through effects on enzyme systems such as the cytochrome P450 (CYP) system are generally not expected for therapeutic monoclonal antibodies. However, monoclonal antibodies that are cytokine modulators may modify the metabolism of drugs that are CYP enzyme substrates through their effects on the regulation pathways of CYP enzymes [32, 42, 43]. Since vedolizumab is gut selective and does not modulate systemic cytokine production [16], the potential for CYP-mediated drug interactions with vedolizumab acting as the perpetrator is considered to be lower than that with drugs that systemically and directly affect cytokines.

Published data show that small-molecule immunomodulators may affect the CL of therapeutic monoclonal antibodies, possibly through an attenuating effect on immunogenicity [32, 42, 44, 45]. No clinical studies have been conducted to directly assess the effect of concomitant therapy on the pharmacokinetics of vedolizumab. However, the effect of concomitant immunomodulator (methotrexate, azathioprine, mercaptopurine) and aminosalicylate therapy on vedolizumab CL_L was assessed through population pharmacokinetic modeling. The effect of each therapy was assessed individually in the model. The findings suggest that these drugs had no clinically relevant effect on vedolizumab CL_L, in contrast to the apparent effect of immunomodulators on the immunogenicity of vedolizumab [29, 46].

In a single-dose phase I study in healthy volunteers, administration of vedolizumab over the dose range of 0.2–10.0 mg/kg resulted in rapid and near complete inhibition of Act-1 and MAdCAM-1-Fc binding to α₄β₇ at all timepoints at which vedolizumab was measurable in serum [25]. Once vedolizumab concentrations were no longer detectable, the inhibition of binding returned to approximately baseline levels. The duration of α₄β₇ receptor saturation was dose dependent.

Saturation of the α₄β₇ receptor was also evaluated following repeat IV infusions in patients with UC or CD over the dose range of 0.5–10.0 mg/kg in phase II studies [26‐28]. After administration of vedolizumab 0.5 or 2.0 mg/kg on days 1 and 29 to patients with UC, saturation of α₄β₇ receptors on >90% of peripheral blood memory T cells was evident at both weeks 4 and 6, as determined using the Act-1 assay [26]. In a second study in patients with UC, administration of vedolizumab 2, 6, or 10 mg/kg on days 1, 15, 29, and 85 resulted in rapid and near-maximal inhibition of MAdCAM-1-Fc binding to α₄β₇ at all doses and timepoints at which vedolizumab was measurable in serum (Fig. 4), consistent with the single-dose healthy volunteer study [27]. MAdCAM-1-Fc binding returned to approximately baseline levels when vedolizumab concentrations were no longer detectable. The duration of α₄β₇ receptor saturation was dose dependent. In patients with CD, near complete saturation of α₄β₇ receptors was observed after administration of vedolizumab 0.5 or 2.0 mg/kg on days 1 and 29 [28]. After the dose on day 29, complete recovery of free α₄β₇ was evident by day 85 for the 0.5 mg/kg group and by day 180 for the 2.0 mg/kg group.

In the GEMINI 1 and GEMINI 2 studies, α₄β₇ receptor saturation was measured using the MAdCAM-1-Fc assay predose at weeks 0, 6, and 52. Data from these studies were pooled with data from phase I and II studies and analyzed using population pharmacokinetic–pharmacodynamic modeling [29]. The inhibition of MAdCAM-1–α₄β₇ binding by vedolizumab was described by a direct-effect sigmoid maximum effect (E _max) model. No formal covariate modeling or model evaluation was conducted. From this model, the vedolizumab serum concentration at half-maximum effect (EC₅₀) was estimated to be 0.093 μg/mL, suggesting that complete receptor saturation was reached at a vedolizumab serum concentration of approximately 1 μg/mL, a concentration considered subtherapeutic [29]. Exposure–efficacy data at week 6 indicate that vedolizumab concentrations of ≤17.1 µg/mL in patients with UC in GEMINI 1 and ≤16 µg/mL in patients with CD in GEMINI 2 during induction were associated with clinical remission rates similar to placebo [48]. These observations support the hypothesis that receptor saturation may be necessary but not sufficient for clinical efficacy of vedolizumab. The discrepancy between the vedolizumab concentrations required for complete receptor saturation and efficacy may be related to the fact that the MAdCAM-1-Fc assay measures α₄β₇ saturation on circulating T cells (as opposed to T cells in inflamed mucosal tissue). However, for another monoclonal antibody that selectively binds to the β₇ subunit of the α₄β₇ and α_Eβ₇ integrins, the drug serum concentration required for maximal saturation of β₇ receptors on peripheral T cells was sufficient for maximal occupancy of β₇ receptors in the colonic mucosa, but maximal receptor occupancy did not correlate with clinical remission [49]. The apparent lack of correlation between receptor occupancy and clinical efficacy for α₄β₇ and α_Eβ₇ integrin antagonists requires further study. The MAdCAM-1 assay demonstrates α₄β₇ saturation from 1 µg/mL, suggesting that receptor saturation in peripheral blood lymphocytes is required for clinical efficacy but cannot achieve it alone [50].

The exposure–efficacy relationships of vedolizumab in patients with UC from GEMINI 1 have been evaluated by grouping the vedolizumab trough (predose) concentrations in quartiles and calculating the associated rates of clinical outcomes. Any confounding factors for baseline covariates were assessed using logistic regression [11, 48]. In these analyses, clinical remission was defined as a complete Mayo score ≤2 points with no individual subscore >1 point; clinical response was defined as a decrease in complete Mayo score ≥3 points and a ≥30% decrease from baseline, with a decrease in rectal bleeding subscore ≥1 point or an absolute rectal bleeding subscore ≤1 point; and mucosal healing was defined as a Mayo endoscopic subscore ≤1 point [11].

The quartile analyses revealed a positive exposure–response relationship for clinical remission, clinical response, and mucosal healing for vedolizumab induction therapy in patients with UC [11, 48]. Vedolizumab concentrations >17.1 µg/mL at week 6 were associated with higher rates of clinical remission than observed with placebo (Fig. 5a). From concentration quartile 1 to quartile 4, the absolute rate increase was approximately 31% for clinical remission, 34% for clinical response, and 43% for mucosal healing at week 6 (Fig. 5a) [48]. Consistent with these data, Mayo endoscopic scores were lower in patients with higher vedolizumab trough concentrations [36].

To account for possible confounding of the unadjusted analyses by baseline covariates, the exposure–efficacy relationships were further explored using logistic regression. Results from the logistic regression analysis confirmed the positive exposure–efficacy relationships for clinical remission and response at week 6 [48]. On average, patients with higher baseline albumin concentrations, lower baseline fecal calprotectin concentrations, and no prior TNF-α antagonist use had a higher probability of clinical remission and response whether they were receiving placebo or vedolizumab. Of these covariates, prior TNF-α antagonist use had the largest effect on the probability of efficacy; the probability of clinical remission at week 6 was approximately 10% higher for patients who were naïve to TNF-α antagonists than for patients who had not responded to this treatment. Vedolizumab concentration was determined to be the strongest factor affecting clinical remission and response rates in patients with UC. After adjusting for confounding factors, increasing the cumulative average concentration through week 6 (C _average) from 35 to 84 µg/mL was associated with a 15% increase in the probability of clinical remission and a 20% increase in the probability of clinical response at week 6.

Consistent with positive exposure–efficacy relationships in patients with UC, the median vedolizumab trough serum concentration at week 6 was higher in remitters [34.7 (95% confidence interval (CI) 31.7–36.6) µg/mL] than in non-remitters [23.7 (22.0–24.8) µg/mL] and also in responders [29.0 (27.3–31.7) µg/mL] than in non-responders [21.5 (20.1–23.3) µg/mL], although some overlap in concentrations was observed between the subgroups [48].

The exposure–efficacy relationships of vedolizumab in patients with CD in the GEMINI 2 and GEMINI 3 studies were also assessed by analyzing the clinical remission and response rates by trough concentration quartile. Similar to the GEMINI 1 analysis, any confounding factors for baseline covariates were assessed using logistic regression [12, 25]. Clinical remission was defined as a CDAI score ≤150 points, and clinical response was defined as a decrease from baseline in CDAI score ≥70 points.

From the quartile analyses, a modest, positive exposure–response relationship was evident for vedolizumab induction therapy, which was shallower than that observed for patients with UC. Vedolizumab concentrations >16.0 µg/mL in GEMINI 2 and >17.1 µg/mL in GEMINI 3 at week 6 were associated with higher rates of clinical remission than those observed with placebo (Fig. 5b, c). From concentration quartile 1 to quartile 4, the absolute rate increase for clinical remission was approximately 14% in GEMINI 2 and only approximately 5% in GEMINI 3 at week 6 (Fig. 5b, c) [48]. However, at week 10, the absolute rate increase from quartile 1 to quartile 4 was approximately 22% for clinical remission in GEMINI 3 (Fig. 5d). These results may be a reflection of the fact that a higher percentage of patients with prior TNF-α antagonist failure were enrolled in GEMINI 3 than in GEMINI 2 (76 versus 58%) [12, 13], possibly representing a more treatment-refractory group of patients who may need a greater exposure of vedolizumab or more time to achieve remission than TNF-α antagonist-naïve patients.

From the logistic regression analysis, which accounted for baseline covariate effects, patients from GEMINI 2 with higher baseline albumin concentrations, lower CRP concentrations, and no prior TNF-α antagonist use, on average, had a higher probability of clinical remission and response whether they were receiving placebo or vedolizumab [48]. Similar to the results for patients with UC, prior TNF-α antagonist use had the largest effect on the probability of efficacy (10% higher probability of clinical remission for treatment-naïve patients). After adjusting for covariates, increasing C _average from 32 to 85 µg/mL corresponded to an approximate 10% increase in the probability of clinical remission and 15% increase in the probability of clinical response at week 6.

Consistent with these results, the median vedolizumab trough concentration at week 6 was higher in remitters [26.8 (95% CI 24.9–30.1) µg/mL] than in non-remitters [23.5 (22.4–24.8) µg/mL] and also in responders [26.8 (25.2–27.7) µg/mL] than in non-responders [22.1 (20.5–23.4) µg/mL] in GEMINI 2 [48]. However, the overlap in concentrations between the subgroups was greater than for patients with UC from GEMINI 1.

Several factors may have contributed to the shallower exposure–efficacy relationships apparent in patients with CD than in patients with UC. Clinical remission rates were higher at week 10 than at week 6 in GEMINI 2 and GEMINI 3, particularly for patients who had previously not responded to TNF-α antagonist therapy [13, 51]. This observation is reflected in the European prescribing information, which states that patients with CD who have not responded to vedolizumab therapy by week 6 may be given an additional dose at week 10 before being assessed for an induction response at week 14 [8]. The exposure–efficacy relationships may have been steeper for patients with CD had a timepoint later than week 6 been evaluated. The steeper exposure–efficacy relationship for clinical remission evident for patients from GEMINI 3 at week 10 than at week 6 supports this hypothesis [48].

In the GEMINI 1 and GEMINI 2 combined population, 56 of 1434 (4%) patients who were treated continuously with vedolizumab for up to 52 weeks were ADA positive at any time during treatment (including the final safety visit); nine of these patients (0.6%) were persistently positive (positive at two or more consecutive visits) and 33 (2.3%) developed neutralizing antibodies [52]. None of the nine persistently positive patients achieved clinical remission at weeks 6 or 52 [7]. As frequently occurs with monoclonal antibodies, the rate of immunogenicity during vedolizumab treatment may have been underestimated. Consistent with this possibility, among the 320 patients who were treated continuously with vedolizumab for up to 52 weeks in GEMINI 1 and GEMINI 2 and who had data available at the final safety visit (week 66), 32 (10%) patients were ADA positive when off drug [52]. While there was an increase in the overall immunogenicity rate off drug compared with on drug, when we examined the impact of the immunogenicity using either the 4% population or the 10–15% population, there was no significant difference between the populations with or without AVAs, suggesting that the impact of immunogenicity was adequately captured.

The increase in the immunogenicity rate off drug compared with on drug suggests that low- to moderate-titer AVAs may have been present and unobservable. However, when comparing the results of the impact of AVAs on clinical safety, efficacy, and pharmacological parameters, only the presence of persistently positive samples resulted in any impact.

An effect of concomitant immunomodulator therapy on the rate of ADA development was evident in those patients who received two doses of vedolizumab during induction and then placebo during maintenance. In the subgroup of these patients who were using immunomodulators at baseline (regardless of other concomitant medication use), only one of 32 patients (3%) was ADA positive (persistently positive) versus 44 of 247 patients (18%) who were not using immunomodulators at baseline [30 patients (12%) were persistently positive] [41, 52]. The impact of immunomodulator coadministration on the rate of ADA development in patients who were administered vedolizumab continuously during induction and maintenance was less obvious, potentially due to a smaller percentage of patients who developed ADA in this group. A total of five of 161 patients (3%) using immunomodulators at baseline were ADA positive (none were persistently positive) versus 51 of 1273 patients (4%) not using immunomodulators at baseline [nine patients (1%) were persistently positive] [41, 52].

In the GEMINI 1 and GEMINI 2 studies, three of 61 patients (5%) who were treated with vedolizumab continuously for up to 52 weeks and who had an investigator-defined infusion-related reaction were persistently ADA positive. Three of the 56 patients (5%) who were persistently ADA positive in these studies experienced an infusion-related reaction [52].