Population pharmacokinetics of tanezumab in phase 3 clinical trials for osteoarthritis pain

AimsThe aims were to 1) develop the pharmacokinetics model to describe and predict observed tanezumab concentrations over time, 2) test possible covariate parameter relationships that could influence clearance and distribution and 3) assess the impact of fixed dosing vs. a dosing regimen adjusted by body weight.MethodsIndividual concentration–time data were determined from 1608 patients in four phase 3 studies conducted to assess efficacy and safety of intravenous tanezumab. Patients received two or three intravenous doses (2.5, 5 or 10 mg) every 8 weeks. Blood samples for assessment of tanezumab PK were collected at baseline, 1 h post‐dose and at weeks 4, 8, 16 and 24 (or early termination) in all studies. Blood samples were collected at week 32 in two studies. Plasma samples were analyzed using a sensitive, specific, validated enzyme‐linked immunosorbent assay.ResultsA two compartment model with parallel linear and non‐linear elimination processes adequately described the data. Population estimates for clearance (CL), central volume (V₁), peripheral volume (V₂), inter‐compartmental clearance, maximum elimination capacity (VM) and concentration at half‐maximum elimination capacity were 0.135 l day^–1, 2.71 l, 1.98 l, 0.371 l day^–1, 8.03 μg day^–1 and 27.7 ng ml^–1, respectively. Inter‐individual variability (IIV) was included on CL, V₁, V₂ and VM. A mixture model accounted for the distribution of residual error. While gender, dose and creatinine clearance were significant covariates, only body weight as a covariate of CL, V₁ and V₂ significantly reduced IIV.ConclusionsThe small increase in variability associated with fixed dosing is consistent with other monoclonal antibodies and does not change risk : benefit.     

Safety, pharmacokinetics, and activity of ABX-EGF, a fully human anti-epidermal growth factor receptor monoclonal antibody in patients with metastatic renal cell cancer.

PURPOSE: To determine the antitumor activity of ABX-EGF, a fully human monoclonal antibody to the epidermal growth factor receptor (EGFr), in previously treated patients with metastatic renal cell carcinoma, and to characterize its toxicity, immunogenicity, pharmacokinetics, and pharmacodynamics. PATIENTS AND METHODS: The antitumor activity, as well as the toxicity, pharmacokinetics, pharmacodynamics, and immunogenicity of ABX-EGF, were assessed. RESULTS: Eighty-eight patients were treated with ABX-EGF doses of 1.0, 1.5, 2.0, or 2.5 mg/kg weekly with no loading dose. EGFr immunostaining was performed on 76 tumor biopsy specimens (86%), and 69 (91%) scored positive. Major responses occurred in three patients, and two patients had minor responses. Forty-four patients (50%) also had stable disease at their first 8-week assessment, and the median progression-free survival (PFS) was 100 days (95% CI, 58 to 140 days). Low hemoglobin and high alkaline phosphatase predicted for short PFS. The principal toxicity, an acneiform rash, occurred in 68%, 95%, 87%, and 100% of patients who received at least three doses of ABX-EGF at 1.0, 1.5, 2.0, and 2.5 mg/kg/wk, respectively. A trend indicated that the severity of the rash may relate to PFS. No human antihuman antibodies were detected. ABX-EGF pharmacokinetics fit a model that incorporated both linear and saturable EGFr-mediated clearance mechanisms, and interindividual variability was low. At 2.5 mg/kg/wk, ABX-EGF concentrations throughout treatment exceeded those estimated to saturate nonlinear clearance and inhibit xenograft growth by 90%. CONCLUSION: ABX-EGF was generally well tolerated. The objective response rate was low in previously treated patients with metastatic renal cell carcinoma. Although skin rash may be a pharmacodynamic marker of drug action, its potential as a surrogate marker of clinical benefit requires further evaluation.     

Comparative study between single dose 600 microg and repeated dose of oral misoprostol for treatment of incomplete abortion

OBJECTIVE: To evaluate and compare the effectiveness and side effects of two regimens of oral misoprostol, single dose (600 microg) and repeated dose (1200 microg), in the treatment of incomplete abortion. METHODS: A prospective randomized controlled trial was conducted. One-hundred women who had incomplete abortion (gestational age < 20 weeks) and consented to randomization by computer-generated randomization model prior to treatment. A single oral 600-microg dose or repeated oral dose after 4 h (total 1200 microg) was given to the randomized women. RESULTS: The overall incidence of complete abortion was 86.9%. This incidence was not statistically different between the single-dose and repeated-dose groups (81.6% vs. 92%, p > 0.05). However, there was a significantly decreased incidence of diarrhea (18.4% vs. 40%, p < 0.05) with the use of single-dose treatment. Overall rate of acceptability and tolerable side effects were 88.9% and 97.9%, respectively. These rates were similar in both groups (87.8% vs. 90% and 98% vs. 98%, p > 0.05). CONCLUSIONS: Oral misoprostol may be a practical alternative in the management of incomplete abortion. Oral misoprostol is acceptable and tolerable to women. Single-dose regimen is as effective as repeated-dose regimen, with a reduction in the incidence of diarrhea.     

Checkpoint-blocker-induced autoimmunity is associated with favourable outcome in metastatic melanoma and distinct T-cell expression profiles

Background Immune checkpoint blockers (ICBs) activate CD8⁺ T cells, eliciting both anti-cancer activity and immune-related adverse events (irAEs). The relationship of irAEs with baseline parameters and clinical outcome is unclear.Methods Retrospective evaluation of irAEs on survival was performed across primary (N = 144) and secondary (N = 211) independent cohorts of patients with metastatic melanoma receiving single agent (pembrolizumab/nivolumab—sICB) or combination (nivolumab and ipilimumab—cICB) checkpoint blockade. RNA from pre-treatment and post-treatment CD8⁺ T cells was sequenced and differential gene expression according to irAE development assessed.Results 58.3% of patients developed early irAEs and this was associated with longer progression-free (PFS) and overall survival (OS) across both cohorts (log-rank test, OS: P < 0.0001). Median survival for patients without irAEs was 16.6 months (95% CI: 10.9–33.4) versus not-reached (P = 2.8 × 10⁻⁶). Pre-treatment monocyte and neutrophil counts, but not BMI, were additional predictors of clinical outcome. Differential expression of numerous gene pathway members was observed in CD8⁺ T cells according to irAE development, and patients not developing irAEs demonstrating upregulated CXCR1 pre- and post-treatment.Conclusions Early irAE development post-ICB is associated with favourable survival in MM. Development of irAEs is coupled to expression of numerous gene pathways, suggesting irAE development in-part reflects baseline immune activation.Subject terms: Immunotherapy, Melanoma     

Low uptake of HIV testing and no HIV positivity in stable serodiscordant heterosexual partners of long-term treated HIV-infected Thais

The objective of this study was to characterize HIV-serodiscordant heterosexual couples and to evaluate acceptance for HIV testing and HIV prevalence in nonindex partners. We conducted a cross-sectional study with quantitative and qualitative components. Two cohorts of 1767 HIV-positive people were screened to identify heterosexual HIV-serodiscordant couples. HIV-positive partners (index) were administered a questionnaire; CD4, viral load (VL), and antiretroviral therapy (ART) history were gathered from clinical records. HIV-negative/unknown status partners (nonindex) were invited for a similar questionnaire and HIV testing. In-depth interviews with three HIV-serodiscordant couples were conducted. Two hundred and ninety-seven index partners agreed to enroll in this study. The median duration of the relationship was 10 years, and 81% were sexually active. All but two index partners were on ART, and 98% had VL < 1000 copies/mL. Only 111 (37%) nonindex partners came for HIV testing, and all of them tested HIV-negative. In addition, only 41% of nonindex partners had HIV testing in the last one year. The main reasons for the nonindex partners not to come for HIV testing were “no interest” (n = 117, 63%) and “nondisclosure of HIV status” (n = 46, 25%). The latter was substantiated and explained by the qualitative outcome of this study, suggesting relation to stigma against HIV-positive people. Our results support the WHO recommendation for starting ART for treatment and prevention in HIV-serodiscordant couples at any CD4 count. Furthermore, we recommend the dissemination of data showing that no HIV transmission in heterosexual couples through sex practice has been observed provided VL is suppressed. This could be a powerful tool for effective fight against stigma and self-stigma in people living with HIV.     

Bipolar Vessel Sealing System Versus Suture Ligation in Selective Neck Dissection

Aim

To evaluate whether the use of electrothermal bipolar vessel sealing system reduces the blood loss and operating time, with lesser complications as compared to suture ligation in selective neck dissection in patients with oral cancer.

Materials and Methods

The study was conducted in the Department of Oral and Maxillofacial Surgery of our institute from January 2015 to December 2016. The sample consisted of 60 patients, divided into Groups I and II with 30 subjects in each. In Group I electrothermal bipolar vessel sealer and in Group II suture ligation were used. The outcome measures recorded were: blood loss, operating time, quality of surgical field, postoperative pain on days 1, 2, and 3, drainage volume at 24, 48, and 72 h, edema, complications, and duration of hospital stay.

Results

There were 36 males and 24 females with a mean age of 50.76 ± 12.6 years. Blood loss was significantly less for Group I than for Group II (p = 0.001); the operating time was significantly less in Group I than in Group II (p = 0.001); Group I had better quality of surgical field (p = 0.001); less pain on postoperative evening, day 2 and day 3 (p < 0.05); and less drainage volume at 24 and 48 h (p < 0.05). Postoperative edema, complications, need for perioperative blood transfusion, and duration of hospital stay postsurgery were similar in both groups.

Conclusion

The electrothermal bipolar vessel sealer was efficacious in terms of reducing blood loss and operating time while providing a better surgical field and patient compliance without increasing the perioperative morbidity.

     

Dose and schedule study of panitumumab monotherapy in patients with advanced solid malignancies.

PURPOSE: This phase 1 study evaluated the safety, pharmacokinetics, and activity of panitumumab, a fully human, IgG2 monoclonal antibody that targets the epidermal growth factor receptor in patients with previously treated epidermal growth factor receptor-expressing advanced solid tumors. EXPERIMENTAL DESIGN: Sequential cohorts were enrolled to receive four i.v. infusions of panitumumab monotherapy at various doses and schedules. Safety was continuously monitored. Serum samples for pharmacokinetic, immunogenicity, and chemistry assessments were drawn at preset intervals. Tumor response was assessed at week 8. RESULTS: Ninety-six patients received panitumumab. Median (range) age was 61 years (32-79 years), and 72 (75%) patients were male. Tumor types were 41% colorectal cancer, 22% prostate, 16% renal, 15% non-small cell lung, 3% pancreatic, 3% esophageal/gastroesophageal, and 1% anal. The overall incidence of grade 3 or 4 adverse events was 32% and 7%, respectively. The incidence of skin-related toxicities was dose dependent. No maximum tolerated dose was reached. No human anti-panitumumab antibodies were detected. No investigator-determined panitumumab infusion-related reactions were reported. Serum panitumumab concentrations were similar in the 2.5 mg/kg weekly, 6.0 mg/kg every 2 weeks, and 9.0 mg/kg every 3 weeks dose cohorts. Five of 39 patients (13%) with colorectal cancer had a confirmed partial response, and 9 of 39 patients (23%) with colorectal cancer had stable disease. CONCLUSIONS: Panitumumab was well tolerated with comparable exposure and safety profiles for the weekly, every 2 weeks, and every 3 weeks administration schedules. Rash and dry skin occurred more frequently in the dose cohorts receiving > or =2.5 mg/kg weekly dose. Panitumumab has single-agent antitumor activity, most notably in patients with advanced colorectal cancer.     

Comparison of Safety,Efficacy, Patient Compliance and Cost-Effectiveness of Transdermal,Oral and Intramuscular Diclofenac for Pain Control Following Oral Surgical Procedures

PurposeTo evaluate transdermal diclofenac in terms of analgesic efficacy, safety, compliance and cost-effectiveness and to compare it with oral tablets and intramuscular (IM) injections following surgical removal of impacted mandibular third molars.Subjects and MethodsA prospective, single-centre, multi-arm parallel, randomized study on subjects undergoing extraction of impacted mandibular third molars was conducted between January 2016 and December 2017. The study included 90 participants, 30 in each group. Participants received the standard once daily (OD) dosages of diclofenac in each group for three post-operative days and were advised to consume paracetamol 500 mg as rescue analgesics if the pain was not alleviated. Outcome measures such as demographics, duration of surgery, post-operative pain, the number of rescue analgesics taken, adverse drug reactions experienced and overall global assessment for three post-operative days were recorded by the participants on a questionnaire.ResultsTransdermal and oral forms achieved similar analgesia on all 3 days. Injectable diclofenac had significantly better pain control on the second and third post-operative days compared to tablets and on the third day compared to transdermal diclofenac. A higher number of rescue analgesics was consumed in oral group on day 1. Gastritis and vomiting were seen in 36.66% and 10% cases, respectively, in oral group. 100% of those in IM group had pain on injection. 6.6% complained of dry skin due to patch, while 3.33% had rash and pruritus. Transdermal group had better overall global assessment by patients with 16.67%, 46.67% and 20% participants reporting excellent, very good and good pain control, respectively. The cost in INR was maximum for the transdermal group.ConclusionTransdermal diclofenac is an excellent alternative to oral and parenteral routes of drug administration in oral surgical procedures with adequate analgesic efficacy, good compliance and fewer side effects.