Comparative pharmacokinetics of subcutaneous trastuzumab administered via handheld syringe or proprietary single-use injection device in healthy males.

PURPOSE: To demonstrate pharmacokinetic (PK) comparability for a single dose of 600 mg subcutaneous (SC) trastuzumab, administered via a novel single-use injection device (SID) or handheld syringe in 119 randomized healthy male subjects. METHODS: The co-primary PK endpoints area under the time-concentration curve from the start of dosing to day 22 (AUC(0-21 days)) and maximum observed trastuzumab serum concentration (C(max)) were dose-normalized and body-weight-adjusted, and compared using geometric mean ratios (GMRs). SID performance, injection site pain, adverse events, and antidrug antibodies (ADAs) were assessed. RESULTS: GMRs and 90 % confidence intervals (CIs) were 1.01 (0.96-1.07) for AUC(0-21 days) and 1.02 (0.96-1.10) for C(max), which fell within the prespecified bioequivalence range (0.80-1.25). No SID quality issues or failures occurred. Adverse events were mostly mild, with no deaths, adverse event-related withdrawals, or life-threatening, cardiac, or serious events reported. The ADA rate was low, and no neutralizing antibodies were detected. CONCLUSIONS: Trastuzumab SC via SID demonstrated comparable PK and safety to handheld syringe administration. SID performance was very satisfactory.

Effects of intravenous zoledronate on bone turnover and bone density persist for at least five years in HIV-infected men.

CONTEXT: In HIV-infected men, the antiresorptive effects of zoledronate persist for at least 2 yr after the second annual dose. OBJECTIVE: Our objective was to determine the duration of action of zoledronate in men. DESIGN AND SETTING: This was 4-yr extension of a 2-yr, double-blind, randomized, placebo-controlled trial at an academic research center. PARTICIPANTS: Participants included 43 HIV-infected men with bone mineral density (BMD) T score below -0.5, 35 of whom entered the extension study. INTERVENTION: Intervention was annual administration of 4 mg iv zoledronate or placebo at baseline and 1 yr and no intervention subsequently. MAIN OUTCOME MEASURES: We evaluated changes in the bone turnover markers, serum osteocalcin and serum C-telopeptide (CTx), and changes in BMD at the lumbar spine, total hip, and total body. RESULTS: There was no time × treatment interaction between 1 and 5 yr after the second zoledronate dose for osteocalcin or CTx (P > 0.4) or any BMD site (P > 0.7). Between 1 and 5 yr after the second dose, on average, osteocalcin was 41% lower (95% confidence interval = 19-62%; P < 0.001), CTx 52% lower (33-71%; P < 0.001), lumbar spine BMD 3.7% greater (0.3-7.0%; P = 0.03), total hip BMD 2.3% greater (0.3-4.3%; P = 0.02), and total body BMD 2.5% greater (0.8-4.1%; P = 0.004) in the zoledronate group than the placebo group. Five years after the second dose, the between-groups differences were 38% (13-62%) for osteocalcin, 49% (20-77%) for CTx, 3.5% (0.7-6.7%) for lumbar spine BMD, 3.4% (1.4-5.4%) for total hip BMD, and 1.6% (0.2-3.1%) for total body BMD. CONCLUSION: The effects of two annual 4-mg doses of zoledronate in men persist for at least 5 yr after the second dose. Larger trials assessing the antifracture efficacy of less frequent dosing of zoledronate are justified.

Stable bone mineral density over 6 years in HIV-infected men treated with highly active antiretroviral therapy (HAART).

OBJECTIVE: Most longitudinal studies of bone mineral density (BMD) in HIV-infected cohorts have been of short duration, typically 1-2 years. Some studies, especially of cohorts treated with highly active antiretroviral therapy (HAART), report short-term stable or increasing BMD, but other studies, often in cohorts initiating HAART, report short-term losses in BMD. We assessed BMD changes over the medium term in HIV-infected men already established on HAART at baseline. DESIGN: Six-year, prospective, longitudinal study. SUBJECTS: Forty-four HIV-infected men treated with HAART and 37 uninfected, healthy controls. MEASUREMENTS: Participants had measurements of BMD at baseline, 2 and 6 years. RESULTS: In the HIV-infected men at baseline, the mean age was 49 years, the mean duration of infection was 8 years, and the mean duration of HAART was 50 months. Over 6 years of follow-up, there was a greater increase in lumbar spine BMD (5·3%, 95% CI 3·8-6·5%) in the HIV-infected men compared with controls (0·3%, 95% CI -1·0 to 1·6%), P < 0·001. There was no difference between the groups in the change in BMD over time at the total hip (HIV group: -0·6%, 95% CI -1·7 to 0·4%, controls -1·0%, 95% CI -2·2 to 0%, P = 0·8) or at the total body (HIV group, 0·3%, 95% CI -0·3 to 1·0%; controls, 0·5%, 95% CI -0·2 to 1·1%, P = 0·15). Lean mass increased in the HIV group, but not in the controls. CONCLUSIONS: There was no evidence of accelerated bone loss over 6 years in middle-aged, HIV-infected men treated with HAART. For such patients, routine monitoring of BMD is not necessary over the short/medium term.

Effects of intravenous zoledronate on bone turnover and BMD persist for at least 24 months.

The duration of the antiresorptive effects of the intravenous bisphosphonate, zoledronate, is not known. Recently, we reported that two annual 4-mg doses of zoledronate suppressed bone turnover and increased BMD in HIV-infected men over 24 mo. We set out to determine the persistence of these effects after two doses of zoledronate. Thirty-three HIV-infected men who completed a randomized trial of 4 mg annual zoledronate (n = 17) or placebo (n = 16) were studied for a further 12 mo, during which time no skeletal therapy was administered. Participants received calcium (400 mg/d) and vitamin D supplements (50,000 IU/mo) for the first 24 mo of the study only. Biochemical markers of bone turnover and BMD were measured every 6 mo. Bone turnover markers were stably suppressed at 24 and 36 mo (12 and 24 mo after the second annual dose of zoledronate, respectively). There were no significant within-group changes in urine N-telopeptide, serum C-telopeptide, and osteocalcin between 24 and 36 mo (p > 0.07), and at each time point, each of the turnover markers was significantly lower in the zoledronate group. There were also no significant between-group differences in the changes in BMD at each site between 24 and 36 mo (p > 0.5), and at each time point, BMD at each site was significantly higher in the zoledronate group. These results suggest that the antiresorptive effects of zoledronate last >12 mo and raise the possibility that zoledronate could be administered less frequently than annually. Randomized trials that address this issue should be performed.

Bone mineral density remains stable in HAART-treated HIV-infected men over 2 years.

OBJECTIVE: Recently we reported that human immunodeficiency virus (HIV)-infected Caucasian men treated with highly active antiretroviral therapy (HAART) have normal weight-adjusted bone mineral density (BMD), in contrast to most other cross-sectional analyses, which have reported low BMD in HIV-infected patients. We have now addressed the question of whether there is accelerated BMD loss over time in HIV-infected men. DESIGN: A 2-year, prospective, longitudinal study. SUBJECTS: Twenty-three HAART-treated, HIV-infected men and 26 healthy controls. MEASUREMENTS: All participants had measurements of BMD and bone-related laboratory parameters at baseline, and a repeat measurement of BMD at 2 years. RESULTS: In the HIV-infected men the mean age was 47 years, the mean duration of infection was 8.2 years, and the mean duration of HAART was 54 months. Over 2 years of follow-up, BMD increased from baseline in the HIV-infected men by 2.6% at the lumbar spine (P = 0.05 vs. baseline), and remained stable at the total hip (mean change 0.1%, P > 0.99) and total body (mean change 0.6%, P = 0.39). Mean changes in BMD in the control group were 1.4% at the lumbar spine, -0.1% at the total hip, and -0.8% at the total body. The HIV-infected men lost less total body BMD than the control group (P = 0.01). In the HIV-infected men, body weight remained stable over 2 years while fat mass decreased and lean mass tended to increase, whereas in the controls, body weight and fat mass increased while lean mass remained stable. CONCLUSIONS: Accelerated bone loss does not occur in HIV-infected men treated with HAART. Monitoring of BMD in HIV-infected men may not be necessary.

Annual zoledronate increases bone density in highly active antiretroviral therapy-treated human immunodeficiency virus-infected men: a randomized controlled trial.

CONTEXT: Recent studies have reported low bone mineral density (BMD) in HIV-infected patients. Annual iv administration of 4 mg zoledronate has been shown to increase BMD and suppress bone turnover in postmenopausal women. OBJECTIVE: The objective of the study was to determine whether annual administration of 4 mg zoledronate will increase BMD in HIV-infected men receiving highly active antiretroviral therapy. DESIGN AND SETTING: A 2-yr randomized placebo-controlled trial was conducted in a clinical research center. PARTICIPANTS: A total of 43 HIV-infected men were treated with highly active antiretroviral therapy for at least 3 months, with BMD T score less than -0.5. INTERVENTION: Participants received annual iv administration of 4 mg zoledronate or placebo. All participants took 400 mg/d calcium and 1.25 mg/month vitamin D. MEASUREMENTS: BMD at the lumbar spine, total hip and total body, and bone turnover markers were measured. RESULTS: At the lumbar spine, BMD increased by 8.9% over 2 yr in the zoledronate group compared with an increase of 2.6% in the control group (P<0.001). At the total hip, BMD increased by 3.8% over 2 yr in the zoledronate group compared with a decrease of 0.8% in the control group (P<0.001). At the total body, BMD increased by 2.3% over 2 yr compared with a decrease of 0.5% in the control group (P<0.001). Urine N-telopeptide decreased by 60% at 3 months in the zoledronate group and thereafter remained stable. CONCLUSIONS: Annual administration of zoledronate is a potent and effective therapy for the prevention or treatment of bone loss in HIV-infected men. The current data provide the first trial evidence of the BMD effects of annual zoledronate beyond 1 yr in any population, as well as being the first reported trial in men.

Bone mineral density is not reduced in HIV-infected Caucasian men treated with highly active antiretroviral therapy.

OBJECTIVE: Recent studies have reported low bone mineral density (BMD) in patients infected with human immunodeficiency virus (HIV). Frequently these findings have been attributed to treatment with highly active antiretroviral therapy (HAART). We sought to determine whether BMD in HIV-infected men treated with HAART for at least 3 months is different from that in healthy controls, and, if so, what HIV-related factors might explain this finding. DESIGN: Cross-sectional analysis. PATIENTS: Fifty-nine HIV-infected Caucasian men treated with HAART, and 118 healthy community-dwelling controls. Each HIV-infected man was age-matched (within 5 years) to two controls. MEASUREMENTS: All participants had measurements of BMD and bone-related laboratory parameters. RESULTS: The mean duration of known HIV infection was 8.5 years, and of treatment with HAART was 52 months. There was no significant difference in mean BMD between groups at the lumbar spine (HIV group: 1.23 g/cm2, controls: 1.25 g/cm2; P = 0.53) or total body (HIV group: 1.18 g/cm2, controls: 1.20 g/cm2; P = 0.09). At the total hip the HIV-infected group had significantly lower BMD than the control group (HIV group: 1.03 g/cm2, controls: 1.09 g/cm2; P = 0.01). The HIV-infected group were, on average, 6.3 kg lighter than the controls. After adjusting for this weight difference, HIV infection was not an independent predictor of BMD at any site (lumbar spine P = 0.79; total hip P = 0.18; total body P = 0.76). CONCLUSIONS: HIV-infected men treated with HAART are lighter than healthy controls. This weight difference is responsible for a small decrement in hip BMD. Overall, BMD is not significantly reduced in HIV-infected Caucasian men treated with HAART.

Outpatient Parenteral Antimicrobial Therapy (OPAT): a review of experience at Auckland Hospital.

AIM: To review the Auckland Hospital Outpatient Parenteral Antimicrobial Therapy (OPAT) Service. METHODS: Patients (>15 years of age) were referred to the Service and assessed for suitability for outpatient therapy by an infectious diseases physician and a specialist nurse. Patient demographics, referring service, site of infection, and infecting organism, antimicrobial agent/s and outcomes of treatment including complications were recorded. RESULTS: Over a 20-month period 100 patients were treated with 107 courses of outpatient parenteral antibiotic therapy. Bone and joint infections accounted for close to two thirds (60%) of the referrals; discitis/osteomyelitis (36%), septic arthritis (14%) and infected metalware/prosthetic joint infections (10%). Staphylococcus aureus was the most frequently isolated organism (42%), and in 21% of cases no organism was identified. In general, antibiotics prescribed were narrow spectrum and all but six patients self-administered up to four times daily. Eighty-eight percent of treatment courses resulted in a cure. Complications related to therapy occurred in 35% of patients. CONCLUSIONS: We have found that parenteral antibiotic therapy can be administered safely and successfully in an outpatient setting despite relatively frequent dosing intervals. The majority of complications were minor, and 88% of patients were cured.