Chapter 4 — Exercises

Items marked † have worked solutions in Appendix M.

A. Recall

4.1 List the five barriers a swallowed peptide must survive, in order.

4.2 † Define bioavailability, half-life, and clearance. Which is the observed quantity and which is the underlying process?

4.3 Name the two routes by which peptides are eliminated from blood, and the engineering strategy that defeats each.

4.4 Approximately what molecular weight is the cutoff below which the kidney filters molecules freely?

4.5 † State the three modifications that convert GLP-1 into semaglutide, with the position and the problem each solves.

4.6 After how many half-lives is a drug conventionally considered essentially gone? Approximately how many are needed to reach steady state on regular dosing?

4.7 What is a permeation enhancer, and which approved peptide drug uses one?

4.8 Define immunogenicity and name the four possible consequences of anti-drug antibodies.

B. Applied pharmacokinetics

4.9 † A peptide has a half-life of 6 hours. Roughly how much remains after 24 hours? What dosing interval would you expect, and why?

4.10 Why is a long half-life both a major advantage and a genuine risk? Give one concrete example of each.

4.11 GLP-1 receptor agonists are titrated upward over weeks. Explain why — and be specific about whether the reason is efficacy or tolerability.

4.12 † A route delivers 1% bioavailability consistently. A second delivers between 0.2% and 4% depending on conditions. Which is the more serious problem for a drug program, and why?

4.13 Semaglutide reaches steady state after roughly a month of weekly dosing. State two practical consequences: one for a patient, one for how a trial must be designed.

C. The semaglutide anchor

4.14 † Explain what each of the three modifications does. Then identify which one has no pharmacological benefit to the patient at all, and explain why it exists anyway.

4.15 Aib is a non-natural amino acid. Explain what it accomplishes, why it is unusual to find a substitution that blocks an enzyme without degrading receptor binding, and what its use implies about how semaglutide must be manufactured.

4.16 Liraglutide uses a similar fatty acid strategy and achieves ~13 hours; semaglutide achieves ~1 week. Both bind albumin. Propose at least two reasons the durations differ so much, and state how you would check.

4.17 † Suppose you defeated only proteolysis and not renal filtration. Predict the resulting half-life qualitatively and explain your reasoning. Now suppose the reverse.

D. The delivery filter

4.18 Apply the five-question delivery filter to each: (a) an oral BPC-157 capsule; (b) a topical copper peptide serum; (c) an intranasal oxytocin spray; (d) subcutaneous semaglutide. For each, note which questions you can answer and which you cannot.

4.19 † A product is sold as a "liposomal oral peptide with enhanced bioavailability." Write the three questions you would ask, in order of how much they would narrow the possibilities.

4.20 A compound with a two-hour half-life is sold with instructions to inject once weekly. Using only Chapter 4, explain what is wrong with this — and identify the one scenario in which it could still make sense.

E. "Explain this to a friend"

4.21 † Explain, in four sentences and without technical vocabulary, why insulin cannot be a pill.

4.22 Your friend asks why the Ozempic pill has so many rules about when to take it and how much water to use, when the injection has almost none. Explain.

4.23 Explain why a peptide drug costs what it costs, in a way that neither defends nor attacks pharmaceutical pricing. Under six sentences.

F. Identify the red flags

4.24 A vendor states: "Our peptide is 99% pure and shipped worldwide via standard post." Using §4.7 and §4.8, identify what this sentence reveals that the vendor probably did not intend to reveal.

4.25 † A product page for an oral peptide states that the compound is "protected by a proprietary delivery matrix for maximum absorption." Rewrite this as the specific claim that would need to be true, then state what study would establish it.

4.26 A gray-market vial is priced at a small fraction of the equivalent prescription drug. Using §4.8, list what the price difference actually represents. Is "the pharmaceutical company is overcharging" a complete explanation?

G. Judgment

4.27 Oral semaglutide throws away roughly 99% of the drug in every tablet. Is that acceptable engineering, wasteful, or both? What considerations would change your answer?

4.28 † §4.9 presents delivery as a "prefilter" applied before evidence. Construct the strongest objection to this approach — a case where applying the delivery filter first would lead you astray.

H. Evidence Dossier extension

4.29 † Complete Field 4 (Pharmacology) for every peptide in your dossier, including the modification line.

4.30 For any dossier peptide whose modification line reads "none," state its native half-life (or "not measured") and compare it to how the compound is actually used. Write one paragraph on any mismatch you find.

4.31 Run the five-question delivery filter on every dossier peptide. Score each out of five for how many questions have documented answers. Rank them. Compare the ranking to your Chapter 1 confidence scores — do they agree?