Clin Pharmacokinet (2012) 51:823–829 DOI 10.1007/s40262-012-0010-0
ORIGINAL RESEARCH ARTICLE
Pharmacokinetic, Pharmacodynamic and Covariate Analysis of Subcutaneous Versus Intravenous Administration of Bortezomib in Patients with Relapsed Multiple Myeloma Philippe Moreau • Ievgenii I. Karamanesht • Natalia Domnikova • Maryna Y. Kyselyova • Kateryna V. Vilchevska • Vadim A. Doronin • Alexander Schmidt • Cyrille Hulin • Xavier Leleu • Dixie-Lee Esseltine • Karthik Venkatakrishnan • Donna Skee • Huaibao Feng • Suzette Girgis • Andrew Cakana • Helgi van de Velde • William Deraedt • Thierry Facon Published online: 25 September 2012 Ó Springer International Publishing Switzerland 2012
Abstract Background and Objectives The proteasome inhibitor bortezomib is approved for the treatment of multiple myeloma (MM) and, in the US, for the treatment of mantle cell lymphoma following at least one prior therapy; the recommended dose and schedule is 1.3 mg/m2 on days 1, 4, 8 and 11 of 21-day cycles, and the approved routes of administration in the US prescribing information are by intravenous and, following a recent update, subcutaneous injection. Findings from a phase III study demonstrated that subcutaneous administration of bortezomib, using the same dose and schedule, resulted in similar efficacy with
an improved systemic safety profile (including significantly lower rates of peripheral neuropathy) versus intravenous bortezomib in patients with relapsed MM. The objectives of this report were to present a comprehensive analysis of the pharmacokinetics and pharmacodynamics of subcutaneous versus intravenous bortezomib, and to evaluate the impact of the subcutaneous administration site, subcutaneous injection concentration and demographic characteristics on bortezomib pharmacokinetics and pharmacodynamics. Patients and Methods Data were analysed from the pharmacokinetic substudy of the randomized phase III MMY3021 study and the phase I CAN-1004 study of subcutaneous
P. Moreau (&) University Hospital, 44093 Nantes cedex 01, France e-mail:
[email protected]
C. Hulin Centre Hospitalier Universitaire Nancy, Nancy, France
I. I. Karamanesht Kiev BMT Centre, Kiev, Ukraine N. Domnikova Hematology Department, State Novosibirsk Regional Clinical Hospital, Novosibirsk, Russia M. Y. Kyselyova Crimean Republic Clinical Oncology Dispensary, Haematology Department, Simferopol, Ukraine K. V. Vilchevska Hematology Department, V.K. Gusak Institute of Urgent and Recovery Surgery, Academy of Medical Science, Donetsk, Ukraine V. A. Doronin City Clinical Hospital #40, Hematology Department, Moscow, Russia A. Schmidt Russian Research Institute of Hematology and Transfusiology, St Petersburg, Russia
X. Leleu T. Facon Hoˆpital Claude Huriez, Centre Hospitalier Re´gional Universitaire de Lille, Lille, France D.-L. Esseltine K. Venkatakrishnan Millennium Pharmaceuticals, Inc., Cambridge, MA, USA D. Skee H. Feng Janssen Research & Development, Raritan, NJ, USA S. Girgis Janssen Research & Development, Titusville, NJ, USA A. Cakana Janssen Research & Development, High Wycombe, Buckinghamshire, UK H. van de Velde W. Deraedt Janssen Research & Development, Beerse, Belgium
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versus intravenous bortezomib in patients aged C18 (MMY3021) or B75 (CAN-1004) years with symptomatic relapsed or refractory MM after 1–3 (MMY-3021) or C1 (CAN-1004) prior therapies. Patients received up to eight 21-day cycles of subcutaneous or intravenous bortezomib 1.3 mg/m2 on days 1, 4, 8 and 11. Pharmacokinetic and pharmacodynamic (20S proteasome inhibition) parameters of bortezomib following subcutaneous or intravenous administration were evaluated on day 11, cycle 1. Results Bortezomib systemic exposure was equivalent with subcutaneous versus intravenous administration in MMY-3021 [mean area under the plasma concentration– time curve from time zero to the last quantifiable timepoint (AUClast): 155 vs. 151 ngh/mL; geometric mean ratio 0.992 (90 % CI 80.18, 122.80)] and comparable in CAN1004 (mean AUClast: 195 vs. 241 ngh/mL); maximum (peak) plasma drug concentration (Cmax) was lower with subcutaneous administration in both MMY-3021 (mean 20.4 vs. 223 ng/mL) and CAN-1004 (mean 22.5 vs. 162 ng/mL), and time to Cmax (tmax) was longer with subcutaneous administration in both studies (median 30 vs. 2 min). Blood 20S proteasome inhibition pharmacodynamic parameters were also similar with subcutaneous versus intravenous bortezomib: mean maximum effect (Emax) was 63.7 versus 69.3 % in MMY-3021 and 57.0 versus 68.8 % in CAN-1004, and mean area under the effect–time curve from time zero to 72 h was 1,714 versus 1,383 %h in MMY-3021 and 1,619 versus 1,283 %h in CAN-1004. Time to Emax was longer with subcutaneous administration in MMY-3021 (median 120 vs. 5 min) and CAN-1004 (median 120 vs. 3 min). Concentration of the subcutaneous injected solution had no appreciable effect on pharmacokinetic or pharmacodynamic parameters. There were no apparent differences in bortezomib pharmacokinetic and pharmacodynamic parameters between subcutaneous administration in the thigh or abdomen. There were also no apparent differences in bortezomib exposure related to body mass index, body surface area or age. Conclusion Subcutaneous administration results in equivalent bortezomib plasma exposure to intravenous administration, together with comparable blood 20S proteasome inhibition pharmacodynamic effects. These findings, together with the non-inferior efficacy of subcutaneous versus intravenous bortezomib demonstrated in MMY-3021, support the use of bortezomib via the subcutaneous route across the settings of clinical use in which the safety and efficacy of intravenous bortezomib has been established.
1 Introduction The proteasome inhibitor bortezomib is approved for the treatment of multiple myeloma (MM) and, in the US, for
P. Moreau et al.
the treatment of mantle cell lymphoma following at least one prior therapy [1, 2]. The recommended dose and schedule is 1.3 mg/m2 on days 1, 4, 8 and 11 of 21-day cycles [1, 2], and the approved routes of administration in the US prescribing information are by intravenous injection and, following a recent update, by subcutaneous injection [2]. Findings from the phase III randomized, non-inferiority MMY-3021 study [3] demonstrated that subcutaneous administration of bortezomib, using the same dose and schedule, was feasible, and resulted in similar efficacy with an improved systemic safety profile (including significantly lower rates of peripheral neuropathy) versus intravenous bortezomib in patients with relapsed MM. These findings built upon an earlier randomized phase I study, CAN-1004 [4]. Here we present a comprehensive analysis of the pharmacokinetics and blood 20S proteasome inhibition pharmacodynamics of subcutaneous versus intravenous bortezomib. We evaluated the impact of the subcutaneous administration site using data from MMY-3021, and of the subcutaneous injection concentration using data from MMY-3021 and CAN-1004. We also evaluated the impact of patient characteristics on bortezomib systemic exposure through exploratory pooled analyses of all available data from both studies.
2 Methods 2.1 Patients and Study Designs The MMY-3021 [3] and CAN-1004 [4] study designs have been published previously and are thus only briefly summarized here. Key eligibility criteria were similar between studies and included the following: symptomatic relapsed or refractory MM after 1–3 (MMY-3021) or C1 (CAN1004) prior therapies; measurable disease; age C18 (MMY-3021) or B75 (CAN-1004) years; and adequate haematological, renal and hepatic function. For both studies, patients were excluded if they had grade C2 peripheral neuropathy. For both studies, all patients provided written informed consent. The studies were approved by institutional review boards or independent ethics committees at each participating institution. Both studies were conducted in accordance with the provisions of the Declaration of Helsinki, the International Conference on Harmonisation, and the Guidelines for Good Clinical Practice. Both the phase III MMY-3021 and phase I CAN-1004 studies were open-label, randomized studies. MMY-3021 enrolled patients between July 2008 and February 2010; clinical data cut-off was August 2010 [3]. CAN-1004 was conducted from January 2006 to February 2007 [4].
PK/PD of SC vs. IV Bortezomib in Relapsed Myeloma
Patients in each study were randomized to receive up to eight 21-day cycles of subcutaneous or intravenous bortezomib 1.3 mg/m2 on days 1, 4, 8 and 11. In MMY-3021, patients with late evolving responses could receive an additional two cycles; in addition, patients with less than complete response (without disease progression) at the end of cycle 4 could also receive dexamethasone 20 mg on days 1, 2, 4, 5, 8, 9, 11 and 12 from cycle 5 onwards. Randomization was stratified by number of prior lines of therapy (1 vs. [1) and International Staging System [5] disease stage in MMY-3021, and was not stratified in CAN-1004. In MMY-3021, 222 patients were randomized (2:1) to receive subcutaneous (n = 148) or intravenous (n = 74) bortezomib; a pharmacokinetic/pharmacodynamic substudy, consisting of 32 patients (subcutaneous, n = 18; intravenous, n = 14), was conducted at selected sites [3]. In CAN-1004, 24 patients were randomized (1:1) to receive subcutaneous (n = 12) or intravenous (n = 12) bortezomib [4]. The subcutaneous injection concentration was 1 mg/mL (bortezomib 3.5 mg reconstituted with 3.5 mL normal [0.9 %] saline) in CAN-1004, but 2.5 mg/mL (bortezomib 3.5 mg reconstituted with 1.4 mL normal [0.9 %] saline) in MMY-3021 [3], in order to reduce the volume injected. Subcutaneous injection sites were the thighs and abdomen, and were rotated for successive injections. In both studies, the intravenous injection concentration was 1 mg/mL. 2.2 Pharmacokinetic and Pharmacodynamic Assessments In MMY-3021, 17 of 18 subcutaneous and 14 of 14 intravenous patients enrolled in the pharmacokinetic/ pharmacodynamic substudy at selected sites were assessable [3]. In CAN-1004, 10 of 12 patients in each arm were included in the pharmacokinetic/pharmacodynamic analyses [4]. Reasons for excluding patients from pharmacokinetic assessment included patients not completing the pharmacokinetic sampling scheme, dose reduction before collecting pharmacokinetic samples, and discontinuation. Blood samples were collected pre-dosing and at multiple timepoints post-dose on day 11 of cycle 1 for pharmacokinetic/pharmacodynamic analyses: immediately (MMY3021) or 30 min (CAN1004) pre-dose; 2, 5, 15 and 30 min post-dose; and 1, 2, 4, 6, 10, 24, 32 (MMY-3021 only), 48 and 72 h post-dose. Pharmacokinetic analyses on day 1 of cycle 1 were not conducted; the pharmacokinetics of bortezomib following multiple subcutaneous dose administration have been previously characterized [4], and given that the pharmacokinetics of bortezomib following repeat dosing were expected to be of primary clinical importance, reflecting systemic exposures in the setting of repeat dose
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administration, the pharmacokinetic substudy in MMY3021 was designed to compare bortezomib pharmacokinetics/pharmacodynamics following subcutaneous versus intravenous dosing on day 11 of cycle 1. Plasma samples were analysed using a validated liquid chromatography– tandem mass spectrometry assay. Whole blood samples were analysed to determine the chymotryptic activity of the proteasome using an established method [6]. All pharmacokinetic parameters were calculated using conventional non-compartmental methods, using WinNonlinÒ Enterprise version 5.2.1 (Pharsight Corp., Mountain View, CA, USA). Pharmacokinetic parameters included the area under the plasma concentration–time curve (AUC) from time zero to the last quantifiable timepoint (AUClast), maximum (peak) plasma drug concentration (Cmax), and time to Cmax (tmax). Pharmacodynamic parameters were calculated by analysis of data on the percentage inhibition of the 20S proteasome in blood over time, which was determined based on the change in proteasome activity from baseline (pre-dose) to subsequent timepoints. Pharmacodynamic parameters included area under the effect–time curve from time zero to 72 h (AUEC72), maximum percentage 20S proteasome inhibition [maximum effect (Emax)] and time to Emax. 2.3 Statistical Methods Arithmetic mean ± standard deviation data were calculated for pharmacokinetic and pharmacodynamic parameters for the individual routes of administration, except tmax and time to Emax, which were presented as median (range) data. Comparison between subcutaneous and intravenous administration of AUClast was based on log-transformed data. Ratio and 90 % confidence interval (CI) data represent the ratio of point estimates of the geometric mean and associated 90 % CI; equivalence was defined as the 90 % CI falling within the standard equivalence limits of 80–125 %. For analyses of demographic covariates and bortezomib systemic exposure, regression and 95 % CI were calculated using SigmaPlotTM (Systat Software, Inc., San Jose, CA, USA) version 11.0.
3 Results 3.1 Pharmacokinetic Parameters Pharmacokinetic analyses demonstrated that bortezomib systemic exposure was equivalent to subcutaneous versus intravenous administration in MMY-3021 (Table 1). The mean AUClast was 155 versus 151 ngh/mL, with a geometric mean ratio of 0.992 (90 % CI 80.18, 122.80), for which the last quantifiable timepoint was 72 h. Systemic
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Table 1 Summary of mean (standard deviation) pharmacokinetic and blood 20S proteasome inhibition pharmacodynamic parameters of bortezomib following subcutaneous or intravenous injection of 1.3 mg/m2 on day 11 of cycle 1 in the MMY-3021 and CAN-1004 studies Parameter
MMY-3021
CAN-1004
SC 2.5 mg/mL
IV 1.0 mg/mL
SC 1.0 mg/mL
IV 1.0 mg/mL
Pharmacokinetic AUClast, ngh/mL
155 (56.8)
151 (42.9)
195 (51.2)
241 (82.0)
Cmax, ng/mL tmax, mina
20.4 (8.87) 30 (5–60)
223 (101) 2 (2–5)
22.5 (5.36) 30 (15–60)
162 (79.9) 2 (2–30)
Pharmacodynamic AUEC72, %h
1,714 (617)
1,383 (767)
1,619 (804)
1,283 (595)
Emax, %
63.7 (10.6)
69.3 (13.2)
57.0 (12.8)
68.8 (6.49)
Time to Emax, mina
120 (30–1440)
5 (2–30)
120 (60–240)
3 (2–30)
AUClast area under the plasma concentration–time curve from time zero to the last quantifiable timepoint, AUEC72 area under the effect-time curve from time zero to 72 h, Cmax maximum (peak) plasma drug concentration, Emax maximum effect, IV intravenous, SC subcutaneous, tmax time to Cmax Median (range)
Bortezomib concentration (ng/mL)
Bortezomib concentration (ng/mL)
exposure was also comparable in CAN-1004, with a mean AUClast of 195 versus 241 ngh/mL with subcutaneous versus intravenous administration. As would be expected, Cmax was lower in both MMY-3021 (mean 20.4 vs. 223 ng/mL, Fig. 1) and CAN-1004 (mean 22.5 vs. 162 ng/mL) with subcutaneous versus intravenous administration. Additionally, tmax was longer with subcutaneous versus intravenous administration in both studies. Comparison of data from MMY-3021, in which the subcutaneous injection concentration was 2.5 mg/mL, and from CAN-1004, in which it was 1.0 mg/mL, both delivering a total dose of 1.3 mg/m2, showed that the subcutaneous injection concentration had no appreciable effect on pharmacokinetic parameters, as shown in Table 1.
1000 100 10
3.2 Pharmacodynamic Parameters Pharmacodynamic parameters of blood 20S proteasome inhibition were also similar with subcutaneous versus intravenous bortezomib (Table 1). The mean Emax with subcutaneous versus intravenous administration was 63.7 versus 69.3 % in MMY-3021 and 57.0 versus 68.8 % in CAN-1004. Similarly, the mean AUEC72 was 1,714 versus 1,383 %h in MMY-3021 (Fig. 2) and 1,619 versus 1,283 %h in CAN-1004. However, reflecting the longer tmax with subcutaneous versus intravenous administration, time to Emax was also longer in both MMY-3021 (median 120 vs. 5 min; Fig. 2) and CAN-1004 (median 120 vs. 3 min).
IV (n = 14) SC (n = 17)
1000
100
100
IV SC
10
80
1 0.1 0.01 0
1
2
3
4
1 0.1
Inhibition (%)
a
60 40 20 0
0.01 0
6
12 18 24 30 36 42 48
54 60 66 72
Time (h) Fig. 1 Mean (standard deviation) plasma bortezomib concentration– time profile following intravenous or subcutaneous injection of 1.3 mg/m2 on day 11, in study MMY-3021. The inset shows the expanded view of the first 4 h. IV intravenous, SC subcutaneous
−20
0
6
12 18 24 30 36 42 48 54 60 66 72 78
Time (h) Fig. 2 Mean (standard deviation) percentage blood 20S proteasome inhibition following subcutaneous or intravenous administration of bortezomib 1.3 mg/m2 on day 11 of cycle 1 in study MMY-3021. IV intravenous, SC subcutaneous
PK/PD of SC vs. IV Bortezomib in Relapsed Myeloma
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3.3 Impact of Injection Site on Pharmacokinetics and Pharmacodynamics of Bortezomib Following Subcutaneous Administration Exploratory analyses of pharmacokinetic and pharmacodynamic parameters in MMY-3021 according to subcutaneous injection site on day 11 of cycle 1 showed no differences between administration in the thigh or abdomen (Tables 2 and 3). There did not seem to be any apparent differences in bortezomib exposure (Fig. 3). 3.4 Impact of Demographic Covariates on Bortezomib Systemic Exposure Exploratory pooled analyses of pharmacokinetic data for subcutaneous and intravenous bortezomib from MMY3021 and CAN-1004 were conducted to explore potential relationships between bortezomib systemic exposure (AUC from time zero to 72 h) and demographic covariates (Fig. 4). There did not seem to be any differences in
Table 2 Mean (standard deviation) pharmacokinetic parameters following subcutaneous injection of bortezomib in MMY-3021, by injection site Injection site
Cmax (ng/mL)
tmax (h)a
AUClast (ngh/mL)
Thigh (n = 11)
17.7 (8.40)
0.50 (0.08–1.00)
171 (62.1)
Abdomen (n = 6)
25.4 (8.08)
0.38 (0.25–1.00)
127 (33.3)
AUClast area under the plasma concentration–time curve from time zero to the last quantifiable timepoint, Cmax maximum (peak) plasma drug concentration, tmax time to Cmax a
Median (range)
Table 3 Mean (standard deviation) blood 20S proteasome inhibition pharmacodynamic parameters following subcutaneous injection of bortezomib in MMY-3021, by injection site Injection site
Emax (%)
Tmax (h)a
AUEC72 (%h)
Thigh (n = 11)
59.1 (6.37)
2.00 (0.50–10)
1700 (484)
Abdomen (n = 6)
72.3 (12.1)
3.00 (1.00–24)
1741 (863)
AUEC72 area under the effect–time curve from time zero to 72 h, Emax maximum effect, Tmax time to Emax a
Median (range)
300
AUC last (ng·h/mL)
Comparison of data from MMY-3021 and CAN-1004 showed that subcutaneous injection concentration had no appreciable effect on pharmacodynamic parameters, as shown in Table 1.
250
200
150
100 50 Thigh (n = 11)
Abdomen (n = 6)
Injection site Fig. 3 AUClast with subcutaneous bortezomib in MMY-3021 by injection site. AUClast area under the plasma concentration–time curve from time zero to the last quantifiable timepoint
bortezomib exposure related to body mass index (Fig. 4a), body surface area (BSA; Fig. 4b) or age (Fig. 4c).
4 Discussion Our findings from the MMY-3021 and CAN-1004 randomized studies of subcutaneous versus intravenous bortezomib in patients with relapsed MM demonstrate that subcutaneous administration results in equivalent bortezomib plasma exposure compared with intravenous administration, together with comparable pharmacodynamic effects. The expected differences between these routes of administration in terms of a lower Cmax and a longer tmax and time to Emax with subcutaneous versus intravenous bortezomib were seen in both studies. Importantly, the results were consistent across the MMY-3021 and CAN-1004 trials. Notably, the site at which the subcutaneous injection was administered and the concentration of the injected solution (2.5 or 1 mg/mL) did not appear to affect the pharmacokinetic and pharmacodynamic parameters of bortezomib following subcutaneous injection, demonstrating the feasibility of using a higher subcutaneous injection concentration (2.5 mg/mL) in order to minimize the volume injected per dose of bortezomib. In both studies, subcutaneous injection sites were the thighs and the abdomen (but not the arms); the absence of any apparent differences in pharmacological parameters between these sites indicates that both represent equally feasible sites for the subcutaneous administration of bortezomib. Additionally, demographic covariates did not appear to have an impact on the systemic exposure with subcutaneous bortezomib, when dosed on the basis of BSA, suggesting the feasibility of this route of administration regardless of a patient’s age or bodyweight.
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AUC last (ng·h/mL)
a
P. Moreau et al. IV (n = 23) SC (n = 27) Regression line 95 % CI
500 400 300 200 100 0 20
25
30
35
40
2
BMI (kg/m )
AUC last (ng·h/mL)
b
500 400 300 200 100 0 1.2
1.4
1.6
1.8
2.0
2.2
2.4
70
80
90
2
BSA (m )
AUC last (ng·h/mL)
c
500 400 300 200 100 0 30
40
50
60
Age (y) Fig. 4 Pooled analyses of subcutaneous and intravenous bortezomib AUClast vs. body mass index (a), body surface area (b) and age (c). AUClast area under the plasma concentration–time curve from time zero to the last quantifiable timepoint, BMI body mass index, BSA body surface area, IV intravenous, SC subcutaneous
It is important to consider these pharmacokinetic and pharmacodynamic data in the context of the reported efficacy and safety data on subcutaneous and intravenous bortezomib [3, 4]. Notably, the similarity of total systemic exposure of bortezomib via subcutaneous and intravenous
administration is reflected in the non-inferior efficacy seen with subcutaneous versus intravenous administration in the MMY-3021 study [3], suggesting that efficacy is related to systemic exposure and not Cmax, which was substantially different between administrative routes. In contrast, the results from MMY-3021 [3] showed that the systemic safety profile of subcutaneous bortezomib was consistent with, and in some aspects improved over, intravenous administration at the dose and schedule studied (1.3 mg/m2 twice weekly for 2 weeks of a 3-week cycle). A similar effect has been reported with alemtuzumab, with lower toxicity noted with subcutaneous versus intravenous alemtuzumab [7]. Specifically, subcutaneous administration of bortezomib resulted in a lower overall incidence of grade C3 adverse events compared with intravenous administration in both the MMY-3021 and CAN-1004 randomized studies [3, 4], and subcutaneous administration also consistently resulted in numerically lower incidences of the most frequently occurring adverse event categories compared with intravenous administration, notably resulting in significantly lower rates of peripheral neuropathy in the MMY-3021 study [3]. These differences in adverse event incidences may be influenced by a number of factors, including differences in baseline susceptibility. However, the small numbers of patients who experienced grade C3 adverse events for whom pharmacokinetic samples were available precluded analysis of associations between lower incidence of adverse events and pharmacokinetic parameters. There are a number of additional aspects of the clinical pharmacology of bortezomib that may be hypothesized to be applicable across the subcutaneous and intravenous administration routes. For example, based on the equivalent systemic exposure following subcutaneous and intravenous administration of bortezomib, the results of all clinical drug–drug interaction studies employing intravenous bortezomib can also be considered applicable to the subcutaneous route of administration. These include the demonstration of no impact on bortezomib pharmacokinetics and pharmacodynamics of co-administration of the strong cytochrome P450 (CYP) 2C19 inhibitor omeprazole [8], the 35 % increase in bortezomib exposure reported with co-administration of the strong CYP3A4 inhibitor ketoconazole [9], and the 45 % reduction in bortezomib exposure seen with co-administration of the strong CYP3A4 inducer rifampicin (rifampin) [10]. Similarly, the findings from clinical pharmacology studies with intravenous bortezomib in patients with renal impairment [11] and hepatic impairment [12], and the resulting dose modification guidelines for moderate and severe hepatic impairment [12], would also be applicable to the subcutaneous route of administration. Thus, posology guidelines for bortezomib contained in the US prescribing information and EU
PK/PD of SC vs. IV Bortezomib in Relapsed Myeloma
summary of product characteristics are equally applicable to both the subcutaneous and intravenous routes of administration [1, 2].
5 Conclusions The non-inferior efficacy of subcutaneous versus intravenous bortezomib in relapsed or refractory MM demonstrated in MMY-3021 [3], together with the equivalent total systemic exposures and similar pharmacodynamics via the subcutaneous and intravenous routes of administration reported in this study, support the use of bortezomib via the subcutaneous route across the settings of clinical use in which the safety and efficacy of intravenous bortezomib has been established. Furthermore, the subcutaneous injection site and concentration of the subcutaneous injected solution did not appear to affect pharmacokinetic and pharmacodynamic parameters, and bortezomib total systemic exposure was not affected by patients’ age or body size parameters. These findings have resulted in an update to the US prescribing information for bortezomib, approved by the US FDA on 23 January 2012, which now includes the subcutaneous route of administration [2], and in the Committee for Medical Products for Human Use of the European Medicines Agency granting a positive opinion recommending approval of subcutaneous administration of bortezomib on 26 June 2012. Acknowledgments These studies were funded by Janssen Research & Development (formerly Johnson & Johnson Pharmaceutical Research & Development, L.L.C.) and Millennium Pharmaceuticals, Inc. Representatives of the sponsors were involved in the study design, data collection, data analysis, data interpretation, and writing and reviewing of the manuscript, as indicated by their inclusion as coauthors. The corresponding author had full access to all data in the studies and had final responsibility for the decision to submit for publication. The authors would like to acknowledge the writing assistance of Steve Hill of FireKite in the development of this manuscript, which was funded by Millennium Pharmaceuticals, Inc., and Janssen Global Services. Conflicts of interest P.M.: advisory board membership, honoraria, Janssen and Millennium Pharmaceuticals, Inc.; I.I.K.: no conflicts of interest; N.D.: no conflicts of interest; M.Y.K.: no conflicts of interest; K.V.V.: no conflicts of interest; V.A.D.: no conflicts of interest; A.S.: no conflicts of interest; C.H.: honoraria, Janssen-Cilag, Celgene; X.L.: institutional grants, lecture fees, Janssen; D.-L.E.: employment, Millennium Pharmaceuticals, Inc., stock ownership, Johnson & Johnson; K.V.: employment, Millennium Pharmaceuticals, Inc.; D.S.: employment, Janssen R&D; H.F.: employment, Janssen R&D; S.G.: employment, Janssen R&D, stock ownership, Johnson & Johnson; A.C.: employment, Janssen R&D; H.vdV.: employment, Janssen R&D, stock ownership, Johnson & Johnson; W.D.: employment,
829 Janssen R&D, stock ownership, Johnson & Johnson; T.F.: speakers bureau, advisory committee, Janssen.
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