THPE036 Pitavastatin 4 mg is Superior to Pravastatin 40 mg on LDL-C Reduction after 12 and 52 Weeks of
Treatment in Patients with HIV Infection and Dyslipidemia with and without Ritonavir-based Therapy
Craig A. Sponseller1, Roger E. Morgan2, Vladimir A. Kryzhanovski3, Judith A. Aberg4
1Kowa Pharmaceuticals America, Inc., Montgomery, AL, USA; 2Kowa Research Institute, Inc., Morrisville, NC, USA; 3Eli Lilly and Company, Indianapolis, IN, USA; 4Icahn School of Medicine at Mount Sinai, New York, NY, USA
Approximately 35.3 million people worldwide are currently living
To determine whether ritonavir use affects the reduction in LDL-C.
Table 1. Baseline Demographics/Characteristics
Figure 2. Week 12: Mean Percent Change from Baseline
Figure 4. Week 52: Mean Percent Change from Baseline
Table 3. Selected Safety Parameters (52-week data)
with HIV/AIDS, including 2.2 million in Europe and 1.1 million in (All Randomized Subjects)
the United States (US).1-3 Pravastatin
Dyslipidemia is a common comorbidity in adults with HIV-1
infection. In the US, for example, dyslipidemia has been reported in 81% of men (median age 47 yrs) and 67% of women (median Number of Subjects (%) age 45 yrs) with HIV-1 infection.4 Treatment-Emergent Adverse Event (TEAE)
Contributing factors include the HIV infection itself as well as
Study Design
antiretroviral (ARV) therapy.5 The most deleterious changes in Treatment-related TEAE lipid levels are seen with ARV combinations that include protease INTREPID was a Phase 4, multicenter, 12-week, randomized,
Treatment-emergent inhibitors (PIs).6 double-blind, double-dummy superiority study followed by a 40-week safety extension study (NCT01301066).
serious adverse event Statins are the most effective agents for reducing LDL-C.7
African-American There was a minimum 4-week washout/dietary stabilization period
Some statins and PIs have contraindications or dosing restrictions
prior to randomization.
Mean % Change
Mean % Change
Discontinuations due to TEAEs
because of the shared metabolic pathway, cytochrome P450 Any discontinuation due Eligible subjects were randomized in a 1:1 ratio, stratified by the
Not Hispanic/Latino, n (%) presence or absence of viral hepatitis B or C, to either pitavastatin Ritonavir is a potent inhibitor of CYP 3A4, and is used to "boost"
Body mass index, kg/m2 Upper abdominal pain 4 mg or pravastatin 40 mg. Dosing was once daily in the morning.
the activity of other PIs.7 Framingham 10-yr risk CHD s Pitavastatin 4 mg: subjects received 1 tablet of pitavastatin 4 mg The drug-drug interaction between certain statins and PIs can
assessment score, % Blood creatine kinase + 1 placebo capsule.
result in elevated statin levels, which lead to an increased risk for Duration of HIV, yrs muscle-related adverse events (e.g., mylagia or rhabdomyolisis).7 s Pravastatin 40 mg: subjects received 1 capsule of pravastatin Hepatitis B or C, n (%) 40  mg (2 tablets of pravastatin 20 mg overencapsulated) + Neither pitavastatin nor pravastatin depend on the CYP enzyme
1 placebo tablet.
CD4 cell count, cells/mm3 system for their metabolism, Figure 3. Week 12: Pitavastatin vs. Pravastatin in
Figure 5. Week 52: Pitavastatin vs. Pravastatin in
7 and neither agent has dose limi- HIV-1 RNA, log copies tations or contraindications when co-administered with PIs, Blood samples for determination of lipid parameters were drawn
LDL-C Reduction (Adjusted for Site, Hepatitis B/C, and
LDL-C Reduction (Adjusted for Site, Hepatitis B/C, and
according to the recent FDA safety communication.
Ritonavir use, n (%) following an overnight fast.
Data are mean (SD) unless otherwise noted.
In adults with dyslipidemia, including those with comorbid
Note: The study period was February 2011-March 2013; this study HIV infection in the INTREPID (HIV-infected patieNts and
Cerebrovascular accident Adults (18–70 yrs) with documented HIV infection and documented
population falls outside the 4 major Statin Benefit groups according to TREatment with PItavastatin vs. pravastatin for Dyslipidemia)
Muscular weakness the 2013 ACC/AHA cholesterol guidelines.
trial, pitavastatin 4 mg has demonstrated significantly greater Most Common (occurring in >5% in either treatment
reductions in LDL-C vs. pravastatin 40 mg after 12 weeks Key inclusion criteria:
group) TEAEs
Table 2. LDL-C Measurements (mITT Population)
52 weeks11,12 of treatment. Reductions in apolipoprotein B, non- s ARV therapy for ≥6 months prior to randomization, with no HDL-C, and total cholesterol were also significantly greater for change in regimen for ≥3 months prior to randomization.
Pitavastatin 4 mg
Pravastatin 40 mg
pitavastatin 4 mg.9-12 s HIV-1 RNA <200 copies/mL and CD4 cell count >200 cells/mm3 LDL-C, mean, mg/dL
The present pre-specified exploratory analysis from INTREPID
for ≥3 months prior to randomization. evaluated the effect of concomitant ritonavir therapy on short- s Fasting serum LDL-C of 130-220 mg/dL (inclusive) and Upper respiratory tract and long-term LDL-C reduction. triglycerides ≤400 mg/dL after the minimum 4-week washout/ dietary stabilization period.
LS Mean % Change
LS Mean % Change
1. Global AIDS Overview. http://aids.gov/federal-resources/around- Key exclusion criteria:
the-world/global-aids-overview/. Accessed 21 May 2014.
LS Mean %Δ = -8.3 s Use of darunavir LS Mean %Δ = -9.8 2. World Health Organization, Europe, Data and statistics. http://www.euro.
Musculoskeletal and Connective Tissue Disorders
s Presence of diabetes or cardiovascular disease statistics. Accessed 21 May 2014.
3. HIV in the United States: At A Glance. http://www.cdc.gov/hiv/resources/ The change from Baseline to Week 12 in LDL-C was
The change from Baseline to Week 52 in LDL-C was
factsheets/us.htm. Accessed 21 May 2014.
Primary: Superiority of pitavastatin 4 mg vs. pravastatin 40 mg
Figure 1. Primary Study Results:
Pain in extremity 4. Buchacz K, et al. Antivir Ther. 2013;18(1):65-75.
based on adjusted mean % change in fasting serum LDL-C from statistically significant (P < 0.001) for each treatment. statistically significant (P < 0.001) for each treatment. LDL-C: Mean Percent Change from Baseline to Week 12
5. Calvo M, Martinez E. Curr Opin HIV AIDS. 2014 May 13 [epub ahead of print].
Baseline to Week 12. 6. Malvestutto CD, Aberg JA. Clev Clin J Med. 2010;77(8):547-556.
and Week 52
Exploratory: Effect of pitavastatin 4 mg and pravastatin 40 mg on
7. Chauvin B, et al. Clin Pharmacokinet. 2013;52(10):815-31.
Virologic failurea Baseline to Week 12
Baseline to Week 52
8. FDA Drug Safety Communication, March 1, 2012. http://www.fda.gov/ LDL-C according to concomitant ritonavir use (either ongoing or aVirologic failure was defined as an HIV-1 RNA value >200 copies/mL and Drugs/DrugSafety/ucm293877.htm. Accessed 21 May 2014. with a start or end date after the first dose of study drug). a >0.3 log increase from baseline. 9. Stender S, et al. Eur J Prev Cardiol. 2013;20(1):40-53.
10. Morgan RE, et al. J Clin Lipidol. 2012;6(3):280-2.
11. Sponseller CA, et al. INTREPID 12-week data. Poster presented at CROI Analyses were conducted using the modified intention-to-treat
(mITT) population, defined as all randomized subjects who received 12. Sponseller CA, et al. INTREPID 52-week data. Poster presented at CROI at least 1 dose of study drug and had at least 1 on-treatment lipid CONClUsiONs
A last observation carried forward (LOCF) methodology and an
-20.5 (15.4)
analysis of covariance (ANCOVA) model were used to determine -20.9 (15.2)
Pitavastatin 4 mg and pravastatin 40 mg
In the overall study population:
% change in LDL-C as the dependent variable and treatment as Mean % Change (SD)
significantly reduced LDL-C after 12 and s Pitavastatin 4 mg demonstrated a superior reduction in LDL-C compared with pravastatin 40 mg in the independent variable, after adjusting for site, viral hepatitis Disclosures: C. Sponseller is an employee of Kowa Pharmaceuticals
52  weeks of treatment, with or without -29.7 (17.4)
HIV-infected adults with dyslipidemia at Week 12.
B/C infection status at randomization (Yes/No), and concomitant -31.1 (15.3)
America, Inc.; R. Morgan is an employee of Kowa Research Institute, ritonavir (ANCOVA, P<0.001).
s The reductions in LDL-C at Week 12 and Week 52 were significantly greater for pitavastatin 4 mg vs. Inc.; V. Kryzhanovski is an employee of Eli Lilly and Company; J. Aberg LS Mean %Δ = -9.8 LS Mean %Δ = -8.4 The reductions in LDL-C were significantly
pravastatin 40 mg.
was an INTREPID study investigator and is a consultant to Kowa For the ritonavir data, where data failed a test of normality, the
greater with pitavastatin — LS mean percent Pharmaceuticals America, Inc. treatments were compared using a nonparametric van Elteren test Use of ritonavir did not change the primary results of the study, i.e., pitavastatin reduced LDL-C significantly
treatment differences: Week 12, -9.8%; to confirm the ANCOVA conclusions; p-values were 2-sided and more than pravastatin after 12 and 52 weeks of therapy. Acknowledgments: Lorraine R. Baer, PharmD (Baer PharMed
Pitavastatin 4 mg was superior to pravastatin 40 mg on
significance was tested. Week 52, -8.3% — van Elteren, P<0.001. Consulting, Ltd.) for content development support.
LDL-C lowering at Week 12 (primary endpoint). Use of ritonavir does not affect the lipid-lowering effect of pitavastatin or pravastatin.
Poster presented at the 20th International AIDS Conference (AIDS 2014), 20–25 July 2014, Melbourne, Australia
Research sponsored by Kowa Pharmaceuticals America, Inc. and Eli Lil y and Company.

Source: http://pag.aids2014.org/EPosterHandler.axd?aid=5485


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SMITHS DETECTION Technical Information Application Brief AB-055LIGHT MICROSCOPY, FT-IR MICROSPECTROSCOPY AND X-RAYDIFFRACTION:COMPLIMENTARY TECHNIQUES FOR SOLID STATE DRUG ANALYSIS The analysis of active pharmaceutical ingredients (APIs) in thesolid state is critically important in drug development andquality assurance, because many drugs are dispensed assolids. Indeed, the APIs may exist in different polymorphiccrystalline or amorphous states, as hydrates or solavates, oreven as salts with various counterions. When a drug substanceis formulated, knowing and controlling the composition andstate of the API is necessary to produce an effective product.Additionally, there are legal implications related to patentclaims and intellectual property that can translate into millions