Human pharmacokinetics and rationale for once-weekly dosing of dalbavancin, a semi-synthetic glycopeptide

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1 Journal of Antimicrobial Chemotherapy (2005) 55, Suppl. S2, ii25 ii30 doi: /jac/dki008 JAC Human pharmacokinetics and rationale for once-weekly dosing of dalbavancin, a semi-synthetic glycopeptide Mary Beth Dorr 1, Daniela Jabes 2, Marco Cavaleri 2, James Dowell 1, Giorgio Mosconi 2, Adriano Malabarba 2, Richard J. White 3 and Timothy J. Henkel 1 * 1 Vicuron Pharmaceuticals, 455 South Gulph Road, King of Prussia, PA; 3 Vicuron Pharmaceuticals, Fremont, CA, USA; 2 Vicuron Pharmaceuticals, Gerenzano, Varese, Italy The selection of a novel weekly dalbavancin dosage regimen was based on pharmacokinetic and pharmacodynamic data from humans and an animal model of infection. The results from the granuloma pouch model of infection suggested that dalbavancin concentrations >_ 5 mg/l are necessary for extended in vivo activity. Serum bactericidal activity assessments demonstrated that dalbavancin serum concentrations of approximately 20 mg/l were bactericidal upon two-fold dilution. These data, coupled with simulations based on the pharmacokinetic profile derived from a clinical study in healthy volunteers, were used to design the weekly regimen studied in the initial efficacy trial. This efficacy study showed that a two-dose weekly regimen was well tolerated and associated with a higher clinical response rate than the comparator regimens. The data collectively support the further study of dalbavancin as a once-weekly regimen for the treatment of infections caused by Gram-positive bacteria. Keywords: dosage regimen, pharmacodynamics, Gram-positive bacteria Introduction Antibiotic dosing regimens are designed to deliver safe and effective drug concentrations to the site of infection and to maintain concentrations above the requisite level for an adequate period of time. These time and concentration requirements differ depending on the class of antimicrobial agent, and can also vary with infecting microorganism and site of infection. When designing a dosage regimen before initiating clinical efficacy trials for a new antibiotic, information about whether the drug exhibits concentration-dependent or time-dependent killing, if known, is taken into consideration. For aminoglycosides and fluoroquinolones, bactericidal activity is concentration-dependent, 1,2 and the dosage regimen attempts to optimize the ratio of the C max or AUC to the MIC. In contrast, b-lactam and macrolide antibiotics work optimally when the dosage regimen maintains the concentration above the causative pathogen s MIC at the site of infection for a significant portion of the dosing interval. The bactericidal activity of glycopeptide antibiotics is generally thought to be time-dependent, although in vitro and animal model studies have demonstrated correlations between all three pharmacodynamic indices (C max /MIC, AUC/MIC and t > MIC) and efficacy. 3 7 Clinical data, however, are limited. One prospective study in patients with Staphylococcus aureus septicaemia showed that the probability of success with teicoplanin therapy was positively correlated with trough plasma concentrations, 8 which can be indicative of either time- or concentration-dependence. Dalbavancin (Vicuron, King of Prussia, PA, USA) is a semisynthetic glycopeptide antibiotic that is obtained by chemical modification of a natural glycopeptide (A 40926) produced by Nonomuria sp. Dalbavancin was selected for clinical development based on its excellent activity against a broad range of clinically important Gram-positive organisms and its unique pharmacokinetics. Dalbavancin is highly active in vitro against staphylococci and streptococci, including resistant isolates, as well as other Gram-positive aerobes and anaerobes In a recent large survey that included 3766 staphylococcal clinical isolates, the dalbavancin MIC 90 against oxacillin-susceptible and -resistant S. aureus and coagulase-negative streptococci isolates was 0.06 mg/l. 13 In vivo efficacy has also been demonstrated in several animal infection models. 9,14,15 The pharmacokinetics are characterized by a long half-life of approximately 7 days. When designing the dalbavancin dosage regimen to be administered to patients in Phase 2 clinical trials, the available clinical pharmacokinetic data and preclinical pharmacodynamic data were assessed. The published clinical data, indicating that trough concentration was correlated with clinical success for teicoplanin, a structurally similar glycopeptide, 8 were also taken into consideration. This paper summarizes the data that were used to design the novel weekly dosing regimen. The results of the first... *Corresponding author. Tel: ; Fax: ; thenkel@vicuron.com... ii25 JAC q The British Society for Antimicrobial Chemotherapy 2005; all rights reserved.

2 efficacy trial carried out with this dosing regimen are also briefly described. M. B. Dorr et al. Granuloma pouch infection model in rats The efficacy of dalbavancin in a granuloma pouch infection model in rats was studied as described previously. 14 This model has previously been used as a guide to the pharmacokinetic and pharmacodynamic behaviour of an antibiotic in tissue fluid. 16 This model of infection has the advantage that bacterial titres and drug concentrations can be measured in the same sample and multiple samples can be obtained from the same animal. After inducing granuloma pouches in groups of five or six Sprague Dawley rats, dorsal pouches were inoculated with 10 5 cfu of bacteria and, 3 h later, a single 2.5, 5 or 10 mg/kg intravenous (iv) dose of dalbavancin was administered. A clinical isolate of methicillin-resistant S. aureus (MRSA), SA 1400, was used. The dalbavancin MIC for this strain in the presence of 50% rat exudate was 8 mg/l and the MBC was mg/l. Serial samples were taken from pouches to determine the number of viable bacteria in the exudate. Dalbavancin concentrations in plasma and exudate were evaluated using a microbiological agar diffusion assay with Bacillus subtilis ATCC 6633 as the indicator organism. Dalbavancin penetrated well into the pouch exudate, reaching a mean peak concentration of 11.1 mg/l 24 h after iv administration of a single 10 mg/kg dose (Figure 1). 14 The dalbavancin concentration in exudate following the 5 and 10 mg/kg doses exceeded 5 and 8 mg/l, respectively, up to 96 h. Elimination occurred at a similar rate from plasma and exudate. The ratio of the area under the plasma concentration time curve (AUC plasma ) to the area under the exudate concentration time curve (AUC exudate ) was 1.01, indicating good penetration of dalbavancin into the granuloma compartment. The in vivo antibacterial activity of dalbavancin was dosedependent. The 2.5 mg/kg dose slowed bacterial growth compared with the untreated control. Bactericidal activity was observed with the 5 and 10 mg/kg doses. The viable count in pouch exudates was reduced by 2 or 3 logs and regrowth was Figure 2. Efficacy of single iv dalbavancin doses of 2.5, 5 and 10 mg/kg against MRSA SA 1400 in the rat granuloma pouch model (adapted with kind permission from Jabes et al. 14 ). Figure 1. Mean (bars = S.D.) concentrations of dalbavancin in MSSAinfected granuloma pouch exudates over 96 h, following iv administration of 2.5, 5 (n = 4 each) or 10 mg/kg (n = 3) (adapted with kind permission from Jabes et al. 14 ). ii26 Figure 3. Mean dalbavancin plasma concentrations following single (a) and multiple (b) 30 min iv infusion doses (reproduced with kind permission from Leighton et al. 18 ).

3 Once-weekly dosing of dalbavancin prevented for up to 4 days following a single 5 mg/kg iv dose, and for 5 days after a single 10 mg/kg iv dose (Figure 2). Human pharmacokinetic study A Phase 1 double-blind, randomized, placebo-controlled, singleand multiple-dose escalation study was conducted to determine the maximum tolerated dose and to examine the pharmacokinetics of dalbavancin in healthy volunteers. 17 Dalbavancin was administered at single iv doses of 140, 220, 350, 500, 630, 840 or 1120 mg over 30 min to three volunteers per dose group. A loading dose/daily maintenance dose regimen of 300/30, 400/40, 600/60, 800/80 or 1000/100 mg was administered iv for 7 days in the multiple-dose cohort. Each dose group included one subject who received placebo infusions. Laboratory and physical examination data were collected and examined for changes from baseline and out-of-range values. Adverse events were evaluated for severity and relationship to the study drug. Plasma and urine samples were assayed for dalbavancin by a validated liquid chromatography tandem mass spectrometry method. Dalbavancin plasma pharmacokinetic profiles were characterized by a rapid decline over 12 h during the distribution phase followed by a slower terminal elimination phase (Figure 3). 18 Dalbavancin pharmacokinetic parameter values for the singledose cohort are shown in Table 1 and values for the multipledose cohort are shown in Table 2. The mean [standard deviation (S.D.)] peak concentration of dalbavancin was 325 (41.1) mg/l at the end of a 30 min infusion of 1120 mg dalbavancin, and 55.4 (8.14) mg/l 6 days after this dose. Dalbavancin had a long mean (S.D.) terminal elimination t 1/2 of 170 (18.6) h across all single-dose groups and a mean (S.D.) apparent volume of distribution of 9.7 (2.0) L. Approximately 35% of the administered dose was excreted unchanged in urine. Dalbavancin was well tolerated in this study. Adverse events were mild and none met the criteria for dose-limiting toxicity. Bactericidal activity in serum from human volunteers In the Phase 1 study described above, serum bactericidal activity (SBA) was measured against a strain of MRSA (S. aureus 3897) in serum samples taken 2, 3 and 7 days post-dose. 18 Two-fold serial dilutions of the serum from each subject were prepared in 50% pooled human serum in microtitre trays. SBA was measured in triplicate following NCCLS 19 procedures. SBA was defined as the highest dilution factor that reduced the initial inoculum by 99.9%. When determined in the presence of 50% human serum, the ranges of dalbavancin MIC (114 runs) and MBC (44 runs) for the strain tested were mg/l and mg/l, respectively. Bactericidal activity remained measurable 7 days after administration in most serum samples from the three volunteers Table 1. Mean (S.D.) dalbavancin pharmacokinetic parameters following administration of a single 30 min iv infusion to healthy subjects (reproduced from Leighton et al. 17 with kind permission) Dose (mg) a Parameter T max (h) (0.289) (0.000) (0.000) (0.000) (0.289) (0.000) (0.000) C max (mg/l) 39.7 (1.64) 65.3 (14.8) 96.1 (6.95) 153 (36.4) 190 (59.0) 243 (11.2) 325 (41.1) AUC (mg h/l) 3251 (86.5) 4955 (562) 8094 (1186) (2001) (4024) (1136) (2447) CL (L/h) (0.001) (0.005) (0.007) (0.006) (0.011) (0.002) (0.004) V ss (L) 10.9 (0.206) 11.3 (1.34) 10.7 (2.34) 8.58 (1.23) 10.5 (3.20) 7.75 (0.556) 8.49 (1.05) t 1/2 (h) 189 (3.59) 188 (17.3) 181 (16.2) 159 (4.99) 172 (16.1) 152 (5.47) 149 (3.60) Fe (%) 33.9 (6.5) 38.4 (12.2) 33.7 (4.5) 28.1 (3.9) 36.8 (10.6) 34.3 (4.0) 35.0 (14.9) Fe, fraction of the dose excreted unchanged in urine. a n = 3 for each dose. Table 2. Mean (S.D.) dalbavancin plasma pharmacokinetic parameters following administration of multiple 30 min iv infusions to healthy subjects (reproduced from Leighton et al. 17 with kind permission) Dose (loading dose/daily maintenance dose, mg) Parameter Day 300/30 400/40 600/60 800/80 a 1000/100 C max (mg/l) (8.11) 77.6 (11.8) 115 (7.81) 131 (31.2) 180 (25.0) C min (mg/l) (4.03) 21.6 (0.569) 30.2 (3.41) 36.5 (7.25) 57.2 (7.75) C max (mg/l) (5.20) 42.3 (7.51) 63.7 (3.15) 67.7 (2.12) 98.9 (18.8) C min (mg/l) (3.49) 30.9 (3.18) 47.1 (2.59) 54.0 (0.707) 77.7 (12.3) AUC 24 (mg h/l) (75.9) 825 (6.30) 1221 (77.3) 1371 (36.7) 1997 (310) CL (L/h) (0.007) (0.005) (0.003) (0.002) (0.007) t 1/2 (h) (14.2) 184 (17.2) 198 (18.7) 198 (13.7) 189 (11.8) a n = 2 on day 7 for this dose group. ii27

4 M. B. Dorr et al. receiving dalbavancin doses of 350 mg, and in all samples from volunteers receiving doses of mg. The median SBA titre and corresponding plasma concentration data for all time points studied in single- and multiple-dose cohorts are shown in Figure SBA titres increased in parallel with plasma concentrations. All samples in which the plasma concentration exceeded 20 mg/l had detectable bactericidal activity upon twofold or greater dilution. Selection of dosage regimen for Phase 2 study The results of the studies summarized above were considered when designing the dosage regimens used in the initial proof-ofconcept study in patients. These results indicated that concentrations of approximately 10 mg/l would be bactericidal against S. aureus, an organism with a high prevalence in complicated Figure 4. Serum bactericidal activity titre versus dalbavancin concentration in samples from healthy volunteers receiving single or multiple doses of dalbavancin (reproduced with kind permission from Leighton et al. 18 ). skin and soft tissue infections, the infection initially under study. Trough plasma concentrations were correlated with clinical success of teicoplanin, 8 so a regimen was chosen that would maintain concentrations above a target concentration for the entire dosing interval. The dosage regimen was chosen to provide bactericidal concentrations up to 7 days post-dose, assuming some variability in pharmacokinetics among patients. Given the long t 1/2 of dalbavancin (approximately 7 days), a weekly dosage regimen was thought to be feasible. Pharmacokinetic simulations indicated that a 1000 mg initial dose followed by a 500 mg dose 1 week later would maintain therapeutic concentrations for 14 days (Figure 5). 20 In the Phase 1 study, doses that produced trough concentrations in this range had been well tolerated. Phase 2 study in patients with skin and skin structure infections A Phase 2, randomized, controlled, proof-of-concept trial was conducted to compare the safety and efficacy of two dalbavancin regimens with standard care. 21 This study enrolled adult patients with skin and skin structure infections involving deep skin structures or requiring surgical intervention. Patients were randomized to one of three arms: dalbavancin 1100 mg iv as a single dose; dalbavancin 1000 mg iv on day 1 and 500 mg iv on day 8; or investigator-specified standard treatment for 7 21 days. The primary end point was clinical response at the follow-up visit in clinically evaluable patients. End of therapy was assumed to be 10 days for the single-dose dalbavancin arm, and 20 days for the two-dose arm. The follow-up assessments were conducted approximately 2 weeks after the end of therapy for each treatment arm. Sixty-two patients were enrolled: 20 in the singledose dalbavancin group and 21 in each of the other arms. The majority (89%) of patients had a deep infection. The most common pathogen was S. aureus, 38% of which were methicillinresistant. The MIC 90 of dalbavancin for the 25 baseline staphylococcal isolates evaluated by the reference laboratory was 0.12 mg/l. Outcomes in the evaluable populations are shown in Table 3. Two doses of dalbavancin resulted in numerically higher response rates than a single dose of dalbavancin or comparator. There was no difference in outcome for MRSA versus methicillin-susceptible S. aureus. Mean (range) plasma concentrations were 30.4 ( ) mg/l immediately before Table 3. Outcomes at follow-up in the evaluable populations (adapted from Seltzer et al. 21 with kind permission of Clinical Infectious Diseases) Treatment group, n/n (%) End point 1-dose dalbavancin 2-dose dalbavancin comparator Clinical success a 8/13 (62) 16/17 (94) 16/21 (76) Microbiological 7/12 (58) 12/13 (92) 12/17 (71) success b Figure 5. Simulation of dalbavancin plasma concentrations for 2 weeks following administration of a 1000 mg iv loading dose and a 500 mg dose 1 week later (reproduced with kind permission from Jordan et al. 20 ). a Defined as resolution of signs and symptoms of infection such that no further antibiotics were needed. b Defined as the eradication or presumed eradication of baseline Grampositive pathogens. ii28

5 Once-weekly dosing of dalbavancin the second dose and 21.2 ( ) mg/l 12 days after the second dose. These concentrations were consistent with the pharmacokinetics observed in healthy volunteers. Dalbavancin was well tolerated. Adverse events were infrequent and similar across study arms. There were no trends in any laboratory abnormalities in the dalbavancin-treated patients. Discussion This review summarizes the rationale for selection of the novel weekly dalbavancin dosage regimen administered to patients in the initial proof-of-concept study in skin and skin structure infections. In vitro studies have demonstrated an effect of serum on the activity of dalbavancin; 9,10 therefore, the impact of protein binding was taken into account when interpreting the results and designing the dosage regimen. The results from the rat granuloma pouch model of infection suggested that drug concentrations >_5 mg/l provide sustained in vivo activity in this compartment in which the protein content is similar to that of plasma. In SBA determination, samples from human subjects in which the plasma concentration was >_ 20 mg/l had detectable bactericidal activity upon >_ 2-fold dilution. Both of these models are appropriate for assessing the amount of total drug needed for activity. The data from the in vivo models, coupled with simulations based on the pharmacokinetic profile derived from the Phase 1 study, were used to calculate both the human dose and schedule studied in the initial efficacy trial. This Phase 2 study showed that a two-dose weekly regimen was associated with a higher clinical response rate than comparator regimens and that this regimen was well tolerated. In conclusion, the in vitro and in vivo and clinical data summarized here confirm the potential utility of dalbavancin as a once-weekly regimen for the treatment of infections caused by Gram-positive bacteria. This weekly regimen may offer certain advantages such as improved patient compliance and reduced resource utilization compared with more frequently dosed antimicrobial agents. Acknowledgements This work was presented in part at: the 42nd Interscience Conference on Antimicrobial Agents and Chemotherapy, Chicago, IL, USA, 2001, Abstracts 951 and 1654, pp. 25 and 68; the 13th European Congress of Clinical Microbiology and Infectious Diseases, Glasgow, UK, 2003, Abstract O143, p. 22; the 41st Annual Meeting of the Infectious Diseases Society of America, San Diego, CA, USA, 2003, Abstract 299, p. 84; and the 16th Annual Meeting of the Surgical Infection Society Europe, Cernobbio, Italy, 2003, Abstract P1. 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