PCEUT 505 Final

Physiologic and Molecular Delivery 

I. Control and Sustain Release 

II. Permeation Enhancement 

III. Modulation of Drug Clearance 

IV. Localization or Targeting to Sites of Action 

V. Molecular Optimization 

VYXEOS® 

-liposomal daunorubicin and cytarabine combination 

- used for treating acute myeloid leukemia.

- biluminar, red

- maintained molar drug ratios of co-loaded

cytarabine and daunorubicin between 5:1 and 9:1 over 24 h

during the blood circulation

- prolonged survival

Significance/Advantages of drug combinations

• Enhanced efficacy through additive or synergistic Effect

• Prevention of drug resistance

• Reduced side effects and toxicity

• Broader spectrum of action

• Improved patient adherence

• Targeting disease heterogeneity

Challenges of drug combinations

• most combo drugs dont have the optimal delivery since different drugs have different optimal delivery methods

• different PK profile and release kinetics

• different therapeutic window

Solutions to problems with drug combinations

I. Control and Sustain Release

II. Permeation Enhancement

III. Modulation of Drug Clearance

IV. Localization or Targeting to Sites of Action

V. Molecular Optimization

TLC-ART

• Targeted long-acting combination antiretroviral therapy

Synchronized delivery

A method of administering multiple drugs simultaneously to achieve optimal therapeutic effects while minimizing the disadvantages of individual drug delivery systems.

maintain plasma levels of both drugs in their therapeutic window

Challenges with LA HIV drug combinations and solutions

1. disparate plasma time course

2. lymphatic drug insufficiency

   solutions

   1. Drug combination nanoparticle

   2. targeting via first-pass to nodes and prolonged plasma profiles

   3. Lopinavir, Ritonavir, Tenofovir

   4. SC - 1 SC = 39 g of LRT

What is drug combination therapy

A product comprised of two or more regulated components

Two or more separate products packaged together in a single

package

Drug, device, biologics

Main goals of Drug combo Delivery

• To improve therapeutic index of a drug by reducing the toxicity

and/or increasing the potency

• To increase patient compliance by ease of use or accessibility

• To reduce frequency of hospital visits or the need of skilled

personnel to provide treatment in chronic therapies

• To automate chronic therapies requiring frequent evaluation of

drug levels

Myeloid Cells

DC, Macrophages, NK cells, granulocytes (4 types)

Lymphoid Cells

B and T cells

Immunogenic DC

• stimulates immune response by activating T cells

• produces pro-inflammatory cytokines: IFN-a, TNF-a, IL-6,12,23.

• Promotes naïve T cells to differentiate into Th1, Th2, Th17, and CD8 T

• Foxp3+ Tregs inhibit the differentiation of immature DC into immunogenic DC.

Tolerogenic DC

• promote immune tolerance by producing Tregs

• secrete anti-inflammatory cytokines like IL-10 and TGF-β.

• Induce Naïve T/B cells to –IL-2 —> Tregs/Breg and Tr-1, promote anergy or apotosis

• Foxp3+ Tregs – suppress immune responses, promote differentiation of immature DC to tDC

Activation Immunotherapies

• checkpoint inhibitors (anti-PD-1 antibodies —> nivolumab)

• CAR-T therapy

• cytokine therapy

• cancer vaccine

Suppression Immunotherapies

• Monoclonal antibodies targeting immune

  components

• Antigen-specific immunotherapies